Download MICROMEDEX® Healthcare Series _ Document

MICROMEDEX®
Healthcare Series :Document
Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
1 of 160
Page 1 Page
of 244
DRUGDEX® Evaluations
FLUVOXAMINE
0.0 Overview
1) Class
a) This drug is a member of the following class(es):
Antidepressant
Central Nervous System Agent
Serotonin Reuptake Inhibitor
2) Dosing Information
a) Fluvoxamine Maleate
1) Adult
a) Depression
1) 50 to 300 mg/day ORALLY
b) Obsessive-compulsive disorder
1) immediate-release, 50 mg/day ORALLY at bedtime; may increase by 50 mg increments every 4-7
days to a MAX dosage of 300 mg/day (usual effective range 100 to 300 mg/day) (Prod Info LUVOX(R)
oral tablets, 2007)
2) extended-release, 100 mg/day ORALLY at bedtime; may increase by 50 mg increments every week
to a MAX dosage of 300 mg/day (usual effective range 100 to 300 mg/day) (Prod Info LUVOX(R) CR
extended-release oral capsules, 2008)
c) Panic disorder
1) 50-300 mg/day ORALLY (mean effective dose is 225 mg/day)
d) Social phobia
1) extended-release, 100 mg/day ORALLY at bedtime; may increase by 50 mg increments every week
to a MAX dosage of 300 mg/day (usual effective range 100 to 300 mg/day) (Prod Info LUVOX(R) CR
extended-release oral capsules, 2008)
2) Pediatric
a) extended-release fluvoxamine maleate has not been evaluated for use in pediatric patients (Prod Info
LUVOX(R) CR extended-release oral capsules, 2008)
b) safety and efficacy of immediate release fluvoxamine maleate has not been studied in patients with
obsessive compulsive disorder (OCD) less than 8 years of age (Prod Info LUVOX(R) oral tablets, 2007)
1) Obsessive-compulsive disorder
a) immediate-release (ages 8-11 yr), 25 mg/day ORALLY at bedtime; may increase by 25 mg
increments every 4-7 days to a MAX dosage of 200 mg/day (usual effective range 50 to 200
mg/day) (Prod Info LUVOX(R) oral tablets, 2007)
b) immediate-release (ages 12-17 yr), 25 mg/day ORALLY at bedtime; may increase by 25 mg
increments every 4-7 days to a MAX dosage of 300 mg/day (usual effective range 50 to 200
mg/day) (Prod Info LUVOX(R) oral tablets, 2007)
3) Contraindications
a) Fluvoxamine Maleate
1) concomitant use with alosetron, pimozide, thioridazine, or tizanidine (Prod Info LUVOX(R) CR extendedrelease oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007)
2) concomitant use with a monoamine oxidase inhibitor (MAOI) or within 14 days following treatment with a
MAOI (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007)
3) hypersensitivity to fluvoxamine maleate or any other component of the product (Prod Info LUVOX(R) CR
extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007)
4) Serious Adverse Effects
a) Fluvoxamine Maleate
1) Bleeding, Abnormal
2) Depression, worsening
3) Extrapyramidal disease
4) Hyponatremia
5) Neuroleptic malignant syndrome
6) Psychotic disorder
7) Seizure
8) Serotonin syndrome
9) Stevens-Johnson syndrome
10) Stevens-Johnson syndrome
11) Suicidal thoughts
12) Syndrome of inappropriate antidiuretic hormone secretion
13) Toxic epidermal necrolysis
14) Withdrawal sign or symptom
5) Clinical Applications
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 1
7/1/2009
MICROMEDEX®
Healthcare Series :Document
Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
2 of 160
Page 2 Page
of 244
a) Fluvoxamine Maleate
1) FDA Approved Indications
a) Obsessive-compulsive disorder
b) Social phobia
2) Non-FDA Approved Indications
a) Depression
b) Panic disorder
1.0 Dosing Information
Drug Properties
Adult Dosage
Pediatric Dosage
1.1 Drug Properties
A) Information on specific products and dosage forms can be obtained by referring to the Tradename List (Product
Index)
B) Synonyms
Fluvoxamine
Fluvoxamine Maleate
C) Physicochemical Properties
1) Molecular Weight
a) Fluvoxamine base: 318.3 (Fleeger, 1994); Fluvoxamine maleate: 434.41 (Canada, 1997)
2) Solubility
a) Systemic: Fluvoxamine maleate is sparingly soluble in water (Prod Info Luvox, 97) and freely soluble in
ethanol (Prod Info Luvox, 97).
1.3 Adult Dosage
Normal Dosage
Dosage in Renal Failure
Dosage in Hepatic Insufficiency
Dosage in Geriatric Patients
1.3.1 Normal Dosage
1.3.1.A Fluvoxamine Maleate
1.3.1.A.1 Oral route
Depression
Obsessive-compulsive disorder
Social phobia
1.3.1.A.1.a Depression
1) Doses of 50 to 300 milligrams/day administered orally have been found effective in clinical trials
(Ottevanger, 1994; Martin et al, 1987a) (Porro et al, 1988). A single night time dose of fluvoxamine
appears to be best tolerated (Siddigui et al, 1985).
1.3.1.A.1.b Obsessive-compulsive disorder
1) Immediate-release Formulation
a) The recommended dose of fluvoxamine maleate for the treatment of obsessions and
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 2
7/1/2009
MICROMEDEX®
Healthcare Series :Document
Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
3 of 160
Page 3 Page
of 244
compulsions in adult patients with obsessive compulsive disorder (OCD) is 50 milligrams (mg)
orally once daily at bedtime initially, titrated by 50 mg increments every 4 to 7 days, as
tolerated, to the target dose range of 100 to 300 mg/day. The maximum dose should not
exceed 300 mg/day. Treatment with fluvoxamine maleate beyond 10 weeks for OCD has not
been studied in controlled trials; therefore, if treatment is necessary beyond 10 weeks,
maintain the patient on the lowest effective dose and periodically reassess the need for
treatment (Prod Info LUVOX(R) oral tablets, 2007).
2) Extended-release Formulation
a) The recommended dose of extended-release fluvoxamine maleate for the treatment of
obsessions and compulsions in adult patients with obsessive compulsive disorder (OCD) is
100 milligrams (mg) orally once daily at bedtime initially, titrated by 50 mg increments every
week, as tolerated, to the target dose range of 100 to 300 mg/day. The maximum dose should
not exceed 300 mg/day. Treatment with extended-release fluvoxamine maleate beyond 12
weeks for OCD has not been studied in controlled trials; therefore, if treatment is necessary
beyond 12 weeks, maintain the patient on the lowest effective dose and periodically reassess
the need for treatment (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Therapy Withdrawal
a) When discontinuing therapy, a gradual reduction in dose is preferred over abrupt cessation
of therapy due to risk of withdrawal symptoms. Monitor for withdrawal symptoms when
stopping fluvoxamine maleate therapy (Prod Info LUVOX(R) CR extended-release oral
capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007).
1.3.1.A.1.c Social phobia
1) The recommended dose of extended-release fluvoxamine maleate for the treatment of social
anxiety disorder (social phobia) in adult patients is 100 milligrams (mg) orally once daily at bedtime
initially, titrated by 50 mg increments every week, as tolerated, to the target dose range of 100 to
300 mg/day. The maximum dose should not exceed 300 mg/day. Treatment with extended-release
fluvoxamine maleate beyond 12 weeks for social anxiety disorder has not been studied in
controlled trials; therefore, if treatment is necessary beyond 12 weeks, maintain the patient on the
lowest effective dose and periodically reassess the need for treatment. When discontinuing
therapy, a gradual withdrawal is preferred to an abrupt cessation of therapy due to risk of
withdrawal symptoms. Monitor for withdrawal symptoms when stopping fluvoxamine maleate
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
1.3.2 Dosage in Renal Failure
A) Fluvoxamine Maleate
1) Renal impairment does not appear to affect the pharmacokinetics of fluvoxamine (Raghoebar &
Roseboom, 1988). However, a low starting dosage along with careful monitoring is recommended,
especially during the first month of treatment.
1.3.3 Dosage in Hepatic Insufficiency
A) Fluvoxamine Maleate
1) Because fluvoxamine undergoes extensive hepatic metabolism, a reduction in the initial dose and slower
dose titration may be required in patients with hepatic insufficiency (Prod Info Luvox(R), 1998); (Harten et al,
1993)(DeBree et al, 1983; Doogan, 1980). A 30% decrease in fluvoxamine clearance was noted in patients
with hepatic insufficiency (Prod Info Luvox(R), 1998).
2) The pharmacokinetics of fluvoxamine were studied in 13 patients with biopsy-proven liver cirrhosis (van
Harten et al, 1993a). They received a single oral 100 mg dose as an enteric-coated tablet and plasma
samples were collected up to one week after administration. The mean elimination half-life was 25 hours
and it increased with higher plasma bilirubin levels although no relationship between bilirubin and AUC was
observed. The AUC was about 50% higher in patients than in healthy volunteers. The authors
recommended that in patients with signs of active liver disease, it is wise to initiate fluvoxamine treatment at
a lower daily dose and to carefully monitor the patient during subsequent dose increases.
1.3.4 Dosage in Geriatric Patients
A) Fluvoxamine Maleate
1) Mean fluvoxamine plasma concentrations are reported to be 40% higher in elderly versus young subjects
following doses of 50 or 100 mg. Fluvoxamine clearance is also reduced by 50% in the elderly. Fluvoxamine
dosage should be slowly titrated in elderly patients (Prod Info Luvox(R), 1998).
1.4 Pediatric Dosage
1.4.1 Normal Dosage
1.4.1.A Fluvoxamine Maleate
1.4.1.A.1 Oral route
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 3
7/1/2009
MICROMEDEX®
Healthcare Series :Document
Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
4 of 160
Page 4 Page
of 244
1.4.1.A.1.a Obsessive-compulsive disorder
1) The recommended dose of fluvoxamine maleate (immediate-release) for the treatment of
obsessions and compulsions in patients aged 8 to 11 years with obsessive compulsive disorder
(OCD) is 25 milligrams (mg) orally once daily at bedtime initially, titrated by 25 mg increments every
4 to 7 days, as tolerated, to the target dose range of 50 to 200 mg/day (maximum dose not to
exceed 200 mg/day). The recommended dose of fluvoxamine maleate (immediate-release) for the
treatment of obsessions and compulsions in patients aged 12 to 17 years with OCD is 25 mg orally
once daily at bedtime initially, titrated by 25 mg increments every 4 to 7 days, as tolerated, to the
target dose range of 50 to 200 mg/day (maximum dose not to exceed 300 mg/day). Treatment with
fluvoxamine maleate beyond 10 weeks for OCD has not been studied in controlled trials; therefore,
if treatment is necessary beyond 10 weeks, maintain the patient on the lowest effective dose and
periodically reassess the need for treatment. When discontinuing therapy, a gradual withdrawal is
preferred to an abrupt cessation of therapy due to risk of withdrawal symptoms. Monitor for
withdrawal symptoms when stopping fluvoxamine maleate therapy (Prod Info LUVOX(R) oral
tablets, 2007).
2) Extended-release fluvoxamine maleate has not been evaluated for use in pediatric patients and is not
indicated for use in this population (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) The safety and efficacy of immediate-release fluvoxamine maleate has not been evaluated in patients
with obsessive compulsive disorder (OCD) less than 8 years of age (Prod Info LUVOX(R) oral tablets,
2007).
2.0 Pharmacokinetics
Onset and Duration
Drug Concentration Levels
ADME
2.1 Onset and Duration
A) Onset
1) Fluvoxamine Maleate
a) Initial Response
1) Obsessions: 3 to 10 weeks (Jenike et al, 1990; Goodman et al, 1990).
2) Depression: 2 to 3 weeks (Wilde et al, 1993a).
2.2 Drug Concentration Levels
A) Fluvoxamine Maleate
1) Peak Concentration
a) Immediate-release, Age Differences
1) Adults, 5.7 nanogram/mL; children (6 to 11 years), 14.8 nanogram/mL; adolescents (12 to 17 years),
4.2 to 6.7 nanogram/mL (Prod Info LUVOX(R) oral tablets, 2007).
a) In a multiple-dose study of immediate-release fluvoxamine maleate tablets in children age 6 to
11 years, adolescents age 12 to 17 years, and adults, peak concentrations were widely variable.
Following oral administration of 100 mg twice daily, children exhibited a mean Cmax of 14.8
nanogram/milliliter (ng/mL) compared to 4.2 ng/mL in adolescents. Following oral administration of
150 mg twice daily, adolescents exhibited a mean Cmax of 6.7 ng/mL compared to 5.7 ng/mL in
adults (Prod Info LUVOX(R) oral tablets, 2007).
b) In a dose proportionality study, following administration of fluvoxamine maleate 100, 200, and
300 mg/day for 10 days in 30 healthy volunteers, the mean maximum plasma concentrations at
steady state were 88, 283, and 546 nanograms/mL, respectively (Prod Info LUVOX(R) oral tablets,
2007).
c) In a pharmacokinetics study, mean maximum plasma concentrations were 40% higher in elderly
patients (66 to 73 years of age) than in younger subjects (19 to 35 years of age) following
administration of immediate-release fluvoxamine 50 mg and 100 mg tablets (Prod Info LUVOX(R)
oral tablets, 2007).
d) Immediate-release, Gender Differences
1) Children (6 to 11 years), females, 28.1 nanogram/milliliter; males, 9.1 nanogram/milliliter
(Prod Info LUVOX(R) oral tablets, 2007).
a) In a multiple-dose study of 100 mg immediate-release fluvoxamine maleate tablets
administered orally twice daily in children age 6 to 11 years and adolescents age 12 to 17
years, female children exhibited a higher mean Cmax compared to male children (28.1
ng/mL versus 9.1 ng/mL, respectively). Gender differences were not noted in adolescents
(Prod Info LUVOX(R) oral tablets, 2007).
b) Extended-release
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 4
7/1/2009
MICROMEDEX®
Healthcare Series :Document
Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
5 of 160
Page 5 Page
of 244
1) In a single-dose crossover study in 28 healthy volunteers, the mean Cmax was 38% lower following
administration of extended-release capsules compared with immediate-release tablets. In a dose
proportionality study, following administration of fluvoxamine maleate extended-release capsules 100,
200, and 300 mg/day in 20 healthy volunteers, the mean maximum plasma concentrations were 47,
161, and 319 nanograms/mL, respectively. The Cmax increased 5.7-fold following the 3-fold increase in
dose from 100 to 300 mg (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
2) In a study of 28 healthy volunteers receiving extended-release fluvoxamine 100 mg, the Cmax was
increased by approximately 60% in females compared with males (Prod Info LUVOX(R) CR extendedrelease oral capsules, 2008).
2) Time to Peak Concentration
a) Immediate-release
1) 3 to 8 hours (Prod Info LUVOX(R) oral tablets, 2007)
a) In a dose proportionality study, following administration of 100, 200, and 300 milligrams/day for
10 days in 30 healthy volunteers, the maximum plasma concentrations at steady state were
reached within 3 to 8 hours (Prod Info LUVOX(R) oral tablets, 2007).
3) Steady State
a) 7 to 10 days (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral
tablets, 2007)
1) Steady-state plasma concentrations were reached following 1 week of dosing with either immediaterelease or extended release fluvoxamine maleate according to dose proportionality studies of 100 to
300 mg/day of either extended-release capsules (n=20), or immediate-release tablets (n=30) (Prod Info
LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007).
2) In additional studies, steady-state plasma concentrations of fluvoxamine were attained in about 10
days of multiple dosing (Harten, 1995; Wilde et al, 1993a; Vries et al, 1992; Wright et al, 1991).
4) Area Under the Curve
a) Immediate-release, Age Differences
1) Adults, 59.4 nanogram x hour/milliliter; children (6 to 11 years), 155.1 nanogram x hour/milliliter;
adolescents (12 to 17 years), 43.9 to 69.6 nanogram x hour/milliliter (Prod Info LUVOX(R) oral tablets,
2007).
a) In a multiple-dose study of immediate-release fluvoxamine maleate tablets in children age 6 to
11 years, adolescents age 12 to 17 years, and adults, AUCs were widely variable. Following oral
administration of 100 mg twice daily, children exhibited a mean AUC of 155.1 nanogram x
hour/milliliter (ng x hr/mL) compared to 43.9 ng x hr/mL in adolescents. Following oral
administration of 150 mg twice daily, adolescents exhibited a mean AUC of 69.6 ng x hr/mL
compared to 59.4 ng x hr/mL in adults (Prod Info LUVOX(R) oral tablets, 2007).
b) Immediate-release, Gender Differences
1) Children (6 to 11 years), females, 293.5 nanogram x hour/milliliter; males, 95.8 nanogram x
hour/milliliter (Prod Info LUVOX(R) oral tablets, 2007).
a) In a multiple-dose study of 100 mg immediate-release fluvoxamine maleate tablets administered
orally twice daily in children age 6 to 11 years and adolescents age 12 to 17 years, female children
exhibited a higher AUC compared to male children (293.5 ng x hr/mL versus 95.8 ng x hr/mL,
respectively). Gender differences were not noted in adolescents (Prod Info LUVOX(R) oral tablets,
2007).
c) Extended-release
1) In a multiple-dose proportionality study, following administration of fluvoxamine maleate extendedrelease capsules 100, 200, and 300 mg/day in 20 healthy volunteers, the AUC increased 5.7-fold
following the 3-fold increase in dose from 100 to 300 mg (Prod Info LUVOX(R) CR extended-release
oral capsules, 2008).
2) In a study of healthy volunteers receiving extended-release fluvoxamine 100 mg, the AUC was
increased by approximately 60% in females (n=13) compared with males (n=15) (Prod Info LUVOX(R)
CR extended-release oral capsules, 2008).
2.3 ADME
Absorption
Distribution
Metabolism
Excretion
Elimination Half-life
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 5
7/1/2009
MICROMEDEX®
Healthcare Series :Document
Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
6 of 160
Page 6 Page
of 244
2.3.1 Absorption
A) Fluvoxamine Maleate
1) Bioavailability
a) Oral, immediate-release: 53% (Prod Info LUVOX(R) oral tablets, 2007); extended-release: 84%
relative to immediate-release (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
1) The absolute bioavailability of fluvoxamine maleate immediate-release tablets is 53% (Prod Info
LUVOX(R) oral tablets, 2007). The bioavailability of fluvoxamine maleate extended-release
capsules is 84% relative to immediate-release tablets (Prod Info LUVOX(R) CR extended-release
oral capsules, 2008).
2) Effects of Food
a) No significant effect (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info
LUVOX(R) oral tablets, 2007).
1) Food causes the mean AUC and Cmax of fluvoxamine to increase only slightly and does not
significantly affect the absorption of fluvoxamine maleate (Prod Info LUVOX(R) CR extendedrelease oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007).
2.3.2 Distribution
A) Distribution Sites
1) Fluvoxamine Maleate
a) Protein Binding
1) 80% (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral
tablets, 2007).
a) Fluvoxamine maleate is 80% bound to plasma protein, primarily albumin, over a
concentration range of 20 to 2000 nanograms/mL (Prod Info LUVOX(R) CR extended-release
oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007).
B) Distribution Kinetics
1) Fluvoxamine Maleate
a) Volume of Distribution
1) 25 L/kg (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R)
oral tablets, 2007).
a) Fluvoxamine maleate exhibits extensive tissue distribution, with a mean apparent Vd of
approximately 25 L/kg (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod
Info LUVOX(R) oral tablets, 2007).
2.3.3 Metabolism
A) Metabolism Sites and Kinetics
1) Fluvoxamine Maleate
a) Liver, extensive (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX
(R) oral tablets, 2007).
1) Fluvoxamine is extensively metabolized in the liver (Prod Info LUVOX(R) CR extended-release
oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007) (DeBree et al, 1983a; Doogan, 1980a)
via oxidative demethylation and deamination (Prod Info LUVOX(R) CR extended-release oral
capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007).
B) Metabolites
1) Fluvoxamine Maleate
a) Fluvoxamine acid (active) (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info
LUVOX(R) oral tablets, 2007).
1) Nine mostly inactive metabolites of fluvoxamine maleate have been identified. One metabolite,
fluvoxamine acid, has a weak effect (1-2 orders of magnitude less potent than the parent
compound) on the inhibition of serotonin uptake (Prod Info LUVOX(R) CR extended-release oral
capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007).
2.3.4 Excretion
A) Kidney
1) Fluvoxamine Maleate
a) Renal Excretion (%)
1) 94% (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral
tablets, 2007; DeBree et al, 1983a; Doogan, 1980a).
a) Following a dose of fluvoxamine maleate 5 mg orally, an average of 94% of drug-related
products was recovered in the urine within 71 hours. Two percent is excreted unchanged in the
urine (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R)
oral tablets, 2007).
b) The mean minimum concentrations were similar after 4 and 6 weeks of treatment with fluvoxamine
maleate 50 mg twice day day (n=13) in renally impaired patients with creatinine clearance of 5 to 45
mL/minute, suggesting no accumulation of fluvoxamine in this group (Prod Info LUVOX(R) CR
extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007).
B) Total Body Clearance
1) Fluvoxamine Maleate
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 6
7/1/2009
MICROMEDEX®
Healthcare Series :Document
Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
7 of 160
Page 7 Page
of 244
a) Hepatic Impairment
1) There was a 30% decrease in fluvoxamine clearance in patients with hepatic dysfunction
compared with healthy subjects in a cross study (Prod Info LUVOX(R) CR extended-release oral
capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007).
b) Elderly
1) In elderly patients the clearance of fluvoxamine was reduced by 50% so initiation of therapy
should be titrated slowly (Prod Info LUVOX(R) oral tablets, 2007)
2.3.5 Elimination Half-life
A) Parent Compound
1) Fluvoxamine Maleate
a) Immediate-release, 15.6 hours (Prod Info LUVOX(R) oral tablets, 2007); extended-release, 16.3
hours (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
1) Immediate-release
a) The mean plasma half-life of fluvoxamine at steady state following multiple dose oral
administration of immediate-release tablets 100 mg/day in young, healthy volunteers was 15.6
hours (Prod Info LUVOX(R) oral tablets, 2007).
b) In a study comparing administration of immediate-release fluvoxamine 50 mg and 100 mg
to elderly patients (66 to 73 years of age) and younger subjects (19 to 35 years of age), the
elimination half-life following multiple doses was 17.4 and 25.9 hours in elderly patients
compared with 13.6 and 15.6 hours in younger subjects, respectively (Prod Info LUVOX(R)
oral tablets, 2007).
2) Extended-release
a) The mean plasma half-life of fluvoxamine following a single oral dose of a 100-mg extended
release capsule in healthy volunteers was 16.3 hours (Prod Info LUVOX(R) CR extendedrelease oral capsules, 2008).
3.0 Cautions
Contraindications
Precautions
Adverse Reactions
Teratogenicity/Effects in Pregnancy/Breastfeeding
Drug Interactions
3.0.A Black Box WARNING
1) Fluvoxamine Maleate
a) Oral (Capsule, Extended Release; Tablet)
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in
children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and
other psychiatric disorders. Anyone considering the use of fluvoxamine maleate extended-release
capsules or any other antidepressant in a child, adolescent, or young adult must balance this risk with
the clinical need. Short-term studies did not show an increase in the risk of suicidality with
antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with
antidepressants compared to placebo in adults aged 65 and older. Depression and certain other
psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages
who are started on antidepressant therapy should be monitored appropriately and observed closely for
clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be
advised of the need for close observation and communication with the prescriber (Prod Info LUVOX(R)
CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007). Fluvoxamine
maleate extended-release capsules are not approved for use in pediatric patients (Prod Info LUVOX(R)
CR extended-release oral capsules, 2008). Fluvoxamine maleate tablets are not approved for use in
pediatric patients except for patients with obsessive compulsive disorder (OCD) (Prod Info LUVOX(R)
oral tablets, 2007).
3.1 Contraindications
A) Fluvoxamine Maleate
1) concomitant use with alosetron, pimozide, thioridazine, or tizanidine (Prod Info LUVOX(R) CR extendedrelease oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007)
2) concomitant use with a monoamine oxidase inhibitor (MAOI) or within 14 days following treatment with a
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 7
7/1/2009
MICROMEDEX®
Healthcare Series :Document
Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
8 of 160
Page 8 Page
of 244
MAOI (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007)
3) hypersensitivity to fluvoxamine maleate or any other component of the product (Prod Info LUVOX(R) CR
extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007)
3.2 Precautions
A) Fluvoxamine Maleate
1) suicidal ideation and behavior or worsening depression has been reported, particularly in children,
adolescents, and young adults during the first few months of therapy or following changes in dosage; monitoring
recommended (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets,
2007)
2) abnormal bleeding, sometimes fatal, has occurred; risk may be increased with concomitant use of drugs that
affect coagulation (eg, NSAIDs, aspirin, warfarin) (Prod Info LUVOX(R) CR extended-release oral capsules,
2008; Prod Info LUVOX(R) oral tablets, 2007)
3) abrupt discontinuation; serious discontinuation symptoms have been reported with abrupt fluvoxamine
maleate withdrawal; monitoring recommended; reduce dose gradually if possible (Prod Info LUVOX(R) CR
extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007)
4) bipolar disorder, in patients at risk (eg, major depressive disorder (MDD) may be the initial presentation of
bipolar disorder); may cause a mixed/manic episode (Prod Info LUVOX(R) CR extended-release oral capsules,
2008; Prod Info LUVOX(R) oral tablets, 2007)
5) concomitant use with antipsychotic agents; may increase the risk of neuroleptic malignant syndrome (NMS)
or NMS-like events (eg, hyperthermia, muscle rigidity, autonomic instability, mental status changes); use with
caution (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007)
6) concomitant use with serotonergic drugs (eg, SSRIs, serotonin-norepinephrine reuptake inhibitors),
diazepam, ramelteon, or serotonin precursors (eg, tryptophan) is not recommended (Prod Info LUVOX(R) CR
extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007)
7) concomitant use with 5-hydroxytryptamine receptor agonists (triptans); risk of serotonin syndrome; monitoring
recommended if concurrent use is clinically warranted (Prod Info LUVOX(R) CR extended-release oral capsules,
2008; Prod Info LUVOX(R) oral tablets, 2007)
8) hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH) has occurred, greater
risk in patients who are volume-depleted, elderly, or receiving concurrent diuretic therapy; discontinue if
symptomatic hyponatremia occurs (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info
LUVOX(R) oral tablets, 2007)
9) liver dysfunction; lower doses may be necessary (Prod Info LUVOX(R) CR extended-release oral capsules,
2008; Prod Info LUVOX(R) oral tablets, 2007)
10) mania, history of; may cause an activation of mania or hypomania (Prod Info LUVOX(R) CR extendedrelease oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007)
11) seizure disorder, history of (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info
LUVOX(R) oral tablets, 2007)
3.3 Adverse Reactions
Cardiovascular Effects
Dermatologic Effects
Endocrine/Metabolic Effects
Gastrointestinal Effects
Hematologic Effects
Hepatic Effects
Immunologic Effects
Musculoskeletal Effects
Neurologic Effects
Ophthalmic Effects
Psychiatric Effects
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 8
7/1/2009
MICROMEDEX®
Healthcare Series :Document
Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
9 of 160
Page 9 Page
of 244
Renal Effects
Reproductive Effects
Respiratory Effects
Other
3.3.1 Cardiovascular Effects
3.3.1.A Fluvoxamine Maleate
Abnormal ECG
Hypotension
Pulse irregular
Sudden cardiac death
3.3.1.A.1 Abnormal ECG
a) Fluvoxamine maleate use was not associated with important changes in ECG variables during shortterm, placebo-controlled trials involving patients with obsessive-compulsive disorder or depression
(Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets,
2007).
b) Premature ventricular contractions (PVCs) not requiring therapy have been occasionally reported
(Garnier et al, 1993).
c) In a pooled analysis of ECG data from several studies, fluvoxamine caused slight increases in the RR, QT, and QTc intervals (Guelfi et al, 1983a; DeWilde & Doogan, 1982; De Wilde et al, 1983a; Benfield
& Ward, 1986b). Fluvoxamine did not change T wave configurations as seen after tricyclic
antidepressant administration (Roos, 1983a).
d) In 25 healthy males, fluvoxamine 50 to 100 mg three times daily for 9 days produced a mean
decrease in heart rate of 5 beats/minute compared with placebo (Robinson & Doogan, 1982).
3.3.1.A.2 Hypotension
a) Incidence: 1% (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R)
oral tablets, 2007)
b) Hypotension was reported in at least 1% of patients with major depressive disorder or obsessivecompulsive disorder who took immediate-release fluvoxamine maleate during premarketing clinical trials
(Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets,
2007).
c) Orthostatic hypotension, which improved upon dose reduction, was reported with fluvoxamine
therapy in patients with obsessive-compulsive disorder (Price et al, 1987).
d) Fluvoxamine did not produce any significant changes in systolic and diastolic blood pressure or
mean arterial pressure in a study using single doses of 50, 75, and 100 mg administered to 17 healthy
volunteers (Wilson et al, 1983).
3.3.1.A.3 Pulse irregular
a) Incidence: 0.1% to 1% (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info
LUVOX(R) oral tablets, 2007)
b) Irregular pulse was reported in 0.1% to 1% of patients with major depressive disorder or obsessivecompulsive disorder who took immediate-release fluvoxamine maleate during premarketing clinical trials
(Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets,
2007).
c) fluvoxamine maleate did not produce any significant changes in pulse rate in a study using single
doses of 50, 75, and 100 mg administered to 17 healthy volunteers (Wilson et al, 1983).
3.3.1.A.4 Sudden cardiac death
a) In a large cohort study including 481,744 persons and 1487 cases of sudden cardiac death occurring
in a community setting, the use of SSRIs was not associated with an increased risk of sudden cardiac
death (rate ratio, 0.95; 95% CI, 0.42 to 2.15). In contrast, users of tricyclic antidepressants in doses of
100 mg or higher (amitriptyline or its equivalent) had a 41% increased rate of sudden cardiac death
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 9
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
10 of 160
Page 10
of 244
(rate ratio, 1.41; 95% CI, 1.02 to 1.95) (Ray et al, 2004).
3.3.2 Dermatologic Effects
3.3.2.A Fluvoxamine Maleate
Alopecia
Rash
Stevens-Johnson syndrome
Sweating
Toxic epidermal necrolysis
3.3.2.A.1 Alopecia
a) Incidence: 0.1% to 1% (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info
LUVOX(R) oral tablets, 2007)
b) Alopecia was reported in between 0.1% and 1% of patients with major depressive disorder or
obsessive-compulsive disorder who took immediate-release fluvoxamine maleate during premarketing
clinical trials (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral
tablets, 2007).
c) A case of patchy baldness was observed following 6 months of therapy with fluvoxamine. A 41-yearold male had taken the medication in varying dosages from 50 to 250 mg/day for treatment of
obsessive-compulsive disorder. Three months following discontinuation of fluvoxamine, regrowth of fine
white hair was noted over the alopecic patches (Parameshwar, 1996).
3.3.2.A.2 Rash
a) In a placebo-controlled study involving pediatric patients with obsessive-compulsive disorder, rash
was reported in 5% or more of patients treated with immediate-release fluvoxamine maleate. This was
at least twice the rate found in placebo-treated patients (Prod Info LUVOX(R) oral tablets, 2007).
3.3.2.A.3 Stevens-Johnson syndrome
a) Stevens-Johnson syndrome has been reported during postmarketing use of immediate-release
fluvoxamine maleate, although a causal relationship has not been established (Prod Info LUVOX(R)
oral tablets, 2007; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3.3.2.A.4 Sweating
a) Incidence: immediate-release, 7%; extended-release (social anxiety disorder), 6%; extended-release
(obsessive-compulsive disorder), 7% (Prod Info LUVOX(R) CR extended-release oral capsules, 2008;
Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
sweating was reported in 7% of fluvoxamine maleate patients (n=892) compared with 3% of placebo
patients (n=778) (Prod Info LUVOX(R) oral tablets, 2007). The use of 100 mg/day to 300 mg/day
extended-release fluvoxamine maleate has been evaluated in short-term, placebo-controlled trials of
social anxiety disorder (SAD) and OCD. For use in SAD treatment, 6% of fluvoxamine maleate patients
(n=279) reported sweating compared with 2% of placebo patients (n=276). For use in OCD treatment,
7% of fluvoxamine maleate patients (n=124) reported sweating compared with less than 1% of placebo
patients (n=124) (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3.3.2.A.5 Toxic epidermal necrolysis
a) Toxic epidermal necrolysis has been reported during postmarketing use of immediate-release
fluvoxamine maleate, although a causal relationship has not been established (Prod Info LUVOX(R)
oral tablets, 2007; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
b) A case of severe toxic epidermal necrolysis (TEN) was reported in a 16-year-old girl following
treatment with fluvoxamine. The patient had been treated with clomipramine 100 mg/day and
clorazepate 50 mg/day, and metoclopramide had been given once. After one week of clomipramine, it
was withdrawn and replaced by fluvoxamine 100 mg/day. Within 8 days of fluvoxamine, the patient
developed a widespread bullous eruption with mucous membrane involvement. Two days later, she
showed epidermal detachment of the trunk, face, and proximal limbs involving 30% of the body surface
area. This rapidly progressed to include 60% of body surface area. Histological examination of the skin
showed total necrosis of the epidermis typical of TEN. Extensive epidemiologic data ruled out other
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 10
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
11 of 160
Page 11
of 244
drugs as causative agents. Fluvoxamine has been previously associated with a case of StevensJohnson syndrome (Wolkenstein et al, 1993).
3.3.3 Endocrine/Metabolic Effects
3.3.3.A Fluvoxamine Maleate
Excessive thirst
Galactorrhea
Hyperglycemia
Hyponatremia
Ineffective thermoregulation
Syndrome of inappropriate antidiuretic hormone secretion
Weight loss
3.3.3.A.1 Excessive thirst
a) There was a two-fold increase in the rate of thirst during studies of obsessive-compulsive disorder
(OCD) treatment compared with studies of OCD and depression (Prod Info LUVOX(R) oral tablets,
2007).
b) Polydipsia occurred in 3 women after taking fluvoxamine 100 mg/day. One patient developed
polydipsia on the second day of treatment. She was also taking levosulpiride and alprazolam. The
symptoms disappeared on withdrawal of fluvoxamine but recurred when the drug was restarted 2 weeks
later. The adverse effect disappeared when the drug was stopped 1 week later. Water ingestion also
increased markedly in a 30-year-old woman with dysthymia and a 40-year-old woman with panic
disorder and agoraphobia shortly after they started fluvoxamine treatment. Symptoms rapidly
disappeared in these 2 women after the drug was discontinued (Benazzi & Mazzoli, 1993).
3.3.3.A.2 Galactorrhea
a) Galactorrhea and amenorrhea associated with fluvoxamine were reported in a 38-year-old woman
with refractory bipolar affective disorder; this patient had been treated for over a decade with several
psychotropic agents. The patient had been maintained for an undetermined length of time on loxapine
150 mg daily, oxazepam 30 mg three times daily, and zopiclone 7.5 mg at bedtime. Fluvoxamine was
prescribed for depression, and the dose was titrated to 150 mg daily while the loxapine dosage was
decreased to 75 mg daily. Six weeks after starting fluvoxamine, she complained of amenorrhea followed
soon by galactorrhea. Thorough evaluation ruled out an underlying organic etiology; however, the
serum prolactin level was 80 mcg/L (normal, 4 to 30 mcg/L). Galactorrhea resolved 3 weeks after
stopping fluvoxamine, and menstruation resumed a week later. The temporal relationship between
fluvoxamine and the onset of galactorrhea and amenorrhea suggests a possible etiologic role for
fluvoxamine (Jeffries et al, 1992). The probable mechanism for SSRI-induced galactorrhea is an
increase in serum prolactin. This may result from direct stimulation of postsynaptic serotonin receptors
in the hypothalamus or presynaptic serotonin receptor mediated inhibition of dopamine release (Bronzo
& Stahl, 1993).
3.3.3.A.3 Hyperglycemia
a) Incidence: less than 0.01% (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod
Info LUVOX(R) oral tablets, 2007)
b) Hyperglycemia was reported in less than 0.1% of patients with major depressive disorder or
obsessive-compulsive disorder who took immediate-release fluvoxamine maleate during premarketing
clinical trials (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral
tablets, 2007).
c) A 60-year-old woman with well-controlled insulin-dependent diabetes developed hyperglycemia
following fluvoxamine administration for the treatment of major depression. Five days following initiation
of fluvoxamine (100 mg/day) therapy, the woman's blood glycemia began to increase significantly
without change in diet or compliance. Glycemia increased from 120 mg/dL at baseline to 210 mg/dL at
days 19 and 21. Hyperglycemia persisted for 9 days before the patient discontinued fluvoxamine and
the blood glycemia returned to baseline level. Twenty-two days later, fluvoxamine therapy was
reinitiated and glycemia increased to the same range as the initial episode. Fluvoxamine was again
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 11
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
12 of 160
Page 12
of 244
stopped and glycemia returned to normal within 2 days (Oswald et al, 2003).
3.3.3.A.4 Hyponatremia
a) Hyponatremia (serum sodium less than 110 mmol/L) has occurred in patients receiving fluvoxamine
maleate, possibly as a result of SIADH. Symptoms included headache, difficulty concentrating, memory
impairment, confusion, weakness, and unsteadiness. Severe hyponatremia signs/symptoms have
included hallucination, syncope, seizure, coma, respiratory arrest, and death. Patients at highest risk
include the elderly, volume-depleted, or those taking diuretics. Consider drug discontinuation with
symptomatic hyponatremia (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info
LUVOX(R) oral tablets, 2007).
b) Of the 63 case reports of fluoxetine-induced SIADH reported to the US Food and Drug
Administration, the majority occurred in patients over 70 years of age. Based on published reports, the
onset of the SIADH was between 3 days and 4 months after starting therapy. Symptoms included
confusion, lethargy, dizziness, fatigue, anorexia, delirium, and abdominal pain. Abnormal laboratory
findings consisted of a decreased serum osmolality (median 251 milliosmoles/liter (mOsm/L); range 214
to 272 mOsm/L), decreased serum sodium concentration (median 118 mEq/L; range 98 to 130
milliequivalents/liter (mEq/L)), and urine osmolality (median 392.5 mOsm/L; 229 to 613 mOsm/L). In all
but 1 case report, the SSRI was stopped, and fluid restriction was required before hyponatremia
resolved; 1 patient was also treated with sodium chloride 3%. Patients in their fifties generally recovered
in 2 to 4 days versus patients in their eighties who required up to 14 days for complete recovery. Of the
6 patients rechallenged with an SSRI, 3 developed a decrease in serum sodium consistent with SIADH,
and 3 tolerated rechallenge without adverse events. In many case reports, inadequate reporting of
symptoms, laboratory results, and exclusion of other causes were NOT included making it difficult to
attribute SIADH to the SSRI (Woo & Smythe, 1997).
3.3.3.A.5 Ineffective thermoregulation
a) Three women developed diaphoresis, shivering, restlessness, anxiety, and subnormal body
temperature, followed by low-grade fever, within 30 minutes of taking a first dose of fluvoxamine 25 mg
in combination with a benzodiazepine (medazepam or ethyl loflazepate) in the evening. The women
were being treated for either panic disorder or anxiety disorder, with associated depressive symptoms.
Symptoms abated and disappeared by the next morning. One woman took a second dose and had the
same experience. In all cases, symptoms did not reappear after discontinuation of fluvoxamine (Okada
& Okajima, 2001).
3.3.3.A.6 Syndrome of inappropriate antidiuretic hormone secretion
a) SIADH with hyponatremia (serum sodium less than 110 mmol/L) has occurred in patients receiving
fluvoxamine maleate. Symptoms included headache, difficulty concentrating, memory impairment,
confusion, weakness, and unsteadiness. Severe hyponatremia signs/symptoms have included
hallucination, syncope, seizure, coma, respiratory arrest, and death. Patients at highest risk include the
elderly, volume-depleted, or those taking diuretics. Consider drug discontinuation with symptomatic
hyponatremia (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R)
oral tablets, 2007).
b) Of the 63 case reports of fluoxetine-induced SIADH reported to the US Food and Drug
Administration, the majority occurred in patients over 70 years of age. Based on published reports, the
onset of the SIADH was between 3 days and 4 months after starting therapy. Symptoms included
confusion, lethargy, dizziness, fatigue, anorexia, delirium, and abdominal pain. Abnormal laboratory
findings consisted of a decreased serum osmolality (median 251 milliosmoles/liter (mOsm/L); range 214
to 272 mOsm/L), decreased serum sodium concentration (median 118 mEq/L; range 98 to 130
milliequivalents/liter (mEq/L)), and urine osmolality (median 392.5 mOsm/L; 229 to 613 mOsm/L). In all
but 1 case report, the SSRI was stopped, and fluid restriction was required before hyponatremia
resolved; 1 patient was also treated with sodium chloride 3%. Patients in their fifties generally recovered
in 2 to 4 days versus patients in their eighties who required up to 14 days for complete recovery. Of the
6 patients rechallenged with an SSRI, 3 developed a decrease in serum sodium consistent with SIADH,
and 3 tolerated rechallenge without adverse events. In many case reports, inadequate reporting of
symptoms, laboratory results, and exclusion of other causes were NOT included making it difficult to
attribute SIADH to the SSRI (Woo & Smythe, 1997).
c) A patient treated with fluvoxamine developed SIADH, which presented as profound confusion. Drug
withdrawal resulted in rapid resolution of the CNS and biochemical abnormalities (McHardy, 1993).
3.3.3.A.7 Weight loss
a) Incidence: immediate-release, at least 1%; extended-release (obsessive-compulsive disorder), 2%
(Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets,
2007)
b) Weight loss was reported in at least 1% of patients with major depressive disorder or obsessivecompulsive disorder (OCD) who took immediate-release fluvoxamine maleate during premarketing
clinical trials. There was a two-fold increase in the rate of weight loss in studies of OCD treatment
compared with studies of OCD and depression (Prod Info LUVOX(R) oral tablets, 2007). The use of 100
mg/day to 300 mg/day extended-release fluvoxamine maleate has been evaluated in short-term,
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 12
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
13 of 160
Page 13
of 244
placebo-controlled trials of social anxiety disorder (SAD) and OCD. Weight loss was not reported during
SAD treatment. For use in OCD treatment, 2% of fluvoxamine maleate patients (n=124) reported weight
loss compared with less than 1% of placebo patients (n=124) (Prod Info LUVOX(R) CR extendedrelease oral capsules, 2008).
c) Decreased appetite and weight loss have occurred in children taking SSRIs, including fluvoxamine
maleate. Regular monitoring of growth is recommended. Weight loss was more frequent in pediatric
OCD patients (n=57) taking immediate-release fluvoxamine maleate than in patients taking placebo
(Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets,
2007).
3.3.4 Gastrointestinal Effects
3.3.4.A Fluvoxamine Maleate
Constipation
Diarrhea
Dysphagia
Flatulence
Gastrointestinal hemorrhage
Indigestion
Loss of appetite
Nausea
Taste sense altered
Vomiting
Xerostomia
3.3.4.A.1 Constipation
a) Incidence: immediate-release, 10%; extended-release (social anxiety disorder), 6%; extendedrelease (obsessive-compulsive disorder), 4% (Prod Info LUVOX(R) CR extended-release oral capsules,
2008; Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
constipation was reported in 10% of fluvoxamine maleate patients (n=892) compared with 8% of
placebo patients (n=778) (Prod Info LUVOX(R) oral tablets, 2007). The use of 100 mg/day to 300
mg/day extended-release fluvoxamine maleate has been evaluated in short-term, placebo-controlled
trials of social anxiety disorder (SAD) and OCD. For use in SAD treatment, 6% of fluvoxamine maleate
patients (n=279) reported constipation compared with 5% of placebo patients (n=276). For use in OCD
treatment, 4% of fluvoxamine maleate patients (n=124) reported constipation compared with less than
1% of placebo patients (n=124) (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
c) Constipation was reported by 18% of fluvoxamine-treated patients (n=222) from pooled data of 10
double-blind, placebo-controlled studies comparing fluvoxamine and imipramine. Constipation was
reported by 20% and 7% of patients treated with imipramine and placebo, respectively (Benfield &
Ward, 1986b).
3.3.4.A.2 Diarrhea
a) Incidence: immediate-release, 11%; extended-release (social anxiety disorder), 14%; extendedrelease (obsessive-compulsive disorder), 18% (Prod Info LUVOX(R) CR extended-release oral
capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
diarrhea was reported in 11% of fluvoxamine maleate patients (n=892) compared with 7% of placebo
patients (n=778) (Prod Info LUVOX(R) oral tablets, 2007). The use of 100 mg/day to 300 mg/day
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 13
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
14 of 160
Page 14
of 244
extended-release fluvoxamine maleate has been evaluated in short-term, placebo-controlled trials of
social anxiety disorder (SAD) and OCD. For use in SAD treatment, 14% of fluvoxamine maleate
patients (n=279) reported diarrhea compared with 5% of placebo patients (n=276). For use in OCD
treatment, 18% of fluvoxamine maleate patients (n=124) reported diarrhea compared with 8% of
placebo patients (n=124) (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3.3.4.A.3 Dysphagia
a) Incidence: immediate-release, 2% (Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
dysphagia was reported in 2% of fluvoxamine maleate patients (n=892) compared with 1% of placebo
patients (n=778). There was a two-fold decrease in the rate of dysphagia in studies of OCD treatment
compared with studies of OCD and depression (Prod Info LUVOX(R) oral tablets, 2007).
3.3.4.A.4 Flatulence
a) Incidence: immediate-release, at least 4% (Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
flatulence was reported in 4% of fluvoxamine maleate patients (n=892) compared with 3% of placebo
patients (n=778) (Prod Info LUVOX(R) oral tablets, 2007).
c) In a placebo-controlled study involving pediatric patients with obsessive-compulsive disorder,
flatulence was reported in 5% or more of patients treated with immediate-release fluvoxamine maleate.
This was at least twice the rate found in placebo-treated patients (Prod Info LUVOX(R) oral tablets,
2007).
3.3.4.A.5 Gastrointestinal hemorrhage
See Drug Consult reference: CONCOMITANT USE OF SSRIs AND NSAIDs - INCREASED RISK OF
GASTROINTESTINAL BLEEDING
3.3.4.A.6 Indigestion
a) Incidence: immediate-release, 10%; extended-release (social anxiety disorder), 10%; extendedrelease (obsessive-compulsive disorder), 8% (Prod Info LUVOX(R) CR extended-release oral capsules,
2008; Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
dyspepsia was reported in 10% of fluvoxamine maleate patients (n=892) compared with 5% of placebo
patients (n=778) (Prod Info LUVOX(R) oral tablets, 2007). The use of 100 mg/day to 300 mg/day
extended-release fluvoxamine maleate has been evaluated in short-term, placebo-controlled trials of
social anxiety disorder (SAD) and OCD. For use in SAD treatment, 10% of fluvoxamine maleate
patients (n=279) reported dyspepsia compared with 4% of placebo patients (n=276). For use in OCD
treatment, 8% of fluvoxamine maleate patients (n=124) reported dyspepsia compared with 5% of
placebo patients (n=124) (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3.3.4.A.7 Loss of appetite
a) Incidence: immediate-release, 6%; extended-release (social anxiety disorder), 14%; extendedrelease (obsessive-compulsive disorder), 13% (Prod Info LUVOX(R) CR extended-release oral
capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
anorexia was reported in 6% of fluvoxamine maleate patients (n=892) compared with 2% of placebo
patients (n=778) (Prod Info LUVOX(R) oral tablets, 2007). The use of 100 mg/day to 300 mg/day
extended-release fluvoxamine maleate has been evaluated in short-term, placebo-controlled trials of
social anxiety disorder (SAD) and OCD. For use in SAD treatment, 14% of fluvoxamine maleate
patients (n=279) reported anorexia compared with 1% of placebo patients (n=276). For use in OCD
treatment, 13% of fluvoxamine maleate patients (n=124) reported anorexia compared with 5% of
placebo patients (n=124) (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
c) Anorexia was reported by 15% of patients receiving fluvoxamine, according to the pooled results of
10 placebo-controlled, double-blind studies comparing fluvoxamine and imipramine (Benfield & Ward,
1986b).
3.3.4.A.8 Nausea
a) Incidence: immediate-release, 40%; extended-release (social anxiety disorder), 39%; extendedrelease (obsessive-compulsive disorder), 34% (Prod Info LUVOX(R) CR extended-release oral
capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
nausea was reported in 40% of fluvoxamine maleate patients (n=892) compared with 14% of placebo
patients (n=778). There was an approximate 25% decrease in the rate of nausea in studies of OCD
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 14
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
15 of 160
Page 15
of 244
treatment compared with studies of OCD and depression (Prod Info LUVOX(R) oral tablets, 2007). The
use of 100 mg/day to 300 mg/day extended-release fluvoxamine maleate has been evaluated in shortterm, placebo-controlled trials of social anxiety disorder (SAD) and OCD. For use in SAD treatment,
39% of fluvoxamine maleate patients (n=279) reported nausea compared with 11% of placebo patients
(n=276). For use in OCD treatment, 34% of fluvoxamine maleate patients (n=124) reported nausea
compared with 13% of placebo patients (n=124) (Prod Info LUVOX(R) CR extended-release oral
capsules, 2008).
c) SSRIs produce nausea and vomiting in 20% to 25% and 2% to 3% of patients, respectively. In the
majority of patients, nausea gradually decreases or resolves over approximately 3 weeks. However, in
others, reduction of the dose or discontinuation of the drug is required. For this group, ondansetron or
cisapride administered for a few weeks may facilitate continued treatment with the SSRI. Limited data
suggest that ondansetron is more effective; however, it is also more expensive. Use of cisapride with
careful monitoring for arrhythmias may be more cost effective and open therapy to a broader group of
patients. The proposed mechanism for SSRI-induced nausea and vomiting is increased serotonin levels
within the chemoreceptor trigger zone and area postrema in the brainstem, the primary areas within the
brain associated with nausea and vomiting (McManis & Talley, 1997).
d) Approximately 12.7% of patients with depression receiving fluvoxamine reported nausea as an
adverse effect during an open, large-scale study of over 5000 patients. Nausea was the stated reason
for withdrawing from this study in 5.6% of all patients (Martin et al, 1987).
e) Event monitoring in Great Britain of fluvoxamine use in 10,401 patients revealed the most commonly
reported individual event to be nausea and vomiting (13%) (Edwards et al, 1994).
3.3.4.A.9 Taste sense altered
a) Incidence: immediate-release, 3%; extended-release, 2% (Prod Info LUVOX(R) CR extendedrelease oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
taste perversion was reported in 3% of fluvoxamine maleate patients (n=892) compared with 1% of
placebo patients (n=778) (Prod Info LUVOX(R) oral tablets, 2007). The use of 100 mg/day to 300
mg/day extended-release fluvoxamine maleate has been evaluated in short-term, placebo-controlled
trials of social anxiety disorder (SAD) and OCD. For use in SAD treatment, 2% of fluvoxamine maleate
patients (n=279) reported taste perversion compared with less than 1% of placebo patients (n=276). For
use in OCD treatment, 2% of fluvoxamine maleate patients (n=124) reported taste perversion compared
with less than 1% of placebo patients (n=124) (Prod Info LUVOX(R) CR extended-release oral
capsules, 2008).
3.3.4.A.10 Vomiting
a) Incidence: immediate-release, 5%; extended-release (social anxiety disorder), 0%; extended-release
(obsessive-compulsive disorder), 6% (Prod Info LUVOX(R) CR extended-release oral capsules, 2008;
Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
vomiting was reported in 5% of fluvoxamine maleate patients (n=892) compared with 2% of placebo
patients (n=778) (Prod Info LUVOX(R) oral tablets, 2007). The use of 100 mg/day to 300 mg/day
extended-release fluvoxamine maleate has been evaluated in short-term, placebo-controlled trials of
social anxiety disorder (SAD) and OCD. Vomiting did not occur during SAD treatment. For use in OCD
treatment, 6% of fluvoxamine maleate patients (n=124) reported vomiting compared with 2% of placebo
patients (n=124) (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
c) SSRIs produce nausea and vomiting in 20% to 25% and 2% to 3% of patients, respectively. In the
majority of patients, nausea gradually decreases or resolves over approximately 3 weeks. However, in
others, reduction of the dose or discontinuation of the drug is required. For this group, ondansetron or
cisapride administered for a few weeks may facilitate continued treatment with the SSRI. Limited data
suggest that ondansetron is more effective; however, it is also more expensive. Use of cisapride with
careful monitoring for arrhythmias may be more cost effective and open therapy to a broader group of
patients. The proposed mechanism for SSRI-induced nausea and vomiting is increased serotonin levels
within the chemoreceptor trigger zone and area postrema in the brainstem, the primary areas within the
brain associated with nausea and vomiting (McManis & Talley, 1997).
d) Vomiting was reported by 3.6% of patients and led to the discontinuation of therapy in 2.8% of all
patients in a open, large-scale study of over 5000 patients with depression (Martin et al, 1987).
e) Event monitoring in Great Britain of fluvoxamine use in 10,401 patients revealed the most commonly
reported individual event to be nausea and vomiting (13%) (Edwards et al, 1994).
3.3.4.A.11 Xerostomia
a) Incidence: immediate-release, 14%; extended-release (social anxiety disorder), 11%; extendedrelease (obsessive-compulsive disorder), 10% (Prod Info LUVOX(R) CR extended-release oral
capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 15
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
16 of 160
Page 16
of 244
dry mouth was reported in 14% of fluvoxamine maleate patients (n=892) compared with 10% of placebo
patients (n=778) (Prod Info LUVOX(R) oral tablets, 2007). The use of 100 mg/day to 300 mg/day
extended-release fluvoxamine maleate has been evaluated in short-term, placebo-controlled trials of
social anxiety disorder (SAD) and OCD. For use in SAD treatment, 11% of fluvoxamine maleate
patients (n=279) reported dry mouth compared with 8% of placebo patients (n=276). For use in OCD
treatment, 10% of fluvoxamine maleate patients (n=124) reported dry mouth compared with 9% of
placebo patients (n=124) (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
c) From pooled data of 10 double-blind, placebo-controlled studies comparing fluvoxamine and
imipramine, dry mouth was experienced by 26% of the patients treated with fluvoxamine (n=222), which
was significantly less than the incidence of 51% in patients who were receiving imipramine (n=221).
Twenty-six percent of patients receiving placebo also complained of dry mouth (Benfield & Ward,
1986b).
d) During an open, large-scale study of over 5000 patients with depression, dry mouth was reported by
3.7% of patients but led to the discontinuation of therapy in only 0.8% of all patients (Martin et al, 1987).
e) Fluvoxamine failed to demonstrate any significant differences in salivary flow when compared to
placebo. The study administered single doses of fluvoxamine 50, 75, and 100 mg to 17 healthy
volunteers (Wilson et al, 1983).
3.3.5 Hematologic Effects
3.3.5.A Fluvoxamine Maleate
3.3.5.A.1 Bleeding, Abnormal
a) In case reports and epidemiological studies, drugs which interfere with serotonin reuptake (eg,
SSRIs and serotonin-norepinephrine-reuptake inhibitors (SNRIs)) have been associated with an
increased incidence of gastrointestinal bleeding. Bleeding events, including ecchymoses, hematomas,
epistaxis, petechiae, gastrointestinal bleeding, and life-threatening hemorrhages have been reported
with SSRI and SNRI use. Because the risk of bleeding may be increased by the concomitant use of
drugs that affect coagulation (eg, NSAIDs, aspirin, warfarin), use caution when these agents are coadministered with fluvoxamine maleate. Additionally, patients receiving concurrent warfarin therapy
should be monitored when fluvoxamine maleate is started or discontinued (Prod Info LUVOX(R) CR
extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007).
b) Epistaxis was more frequent in pediatric obsessive-compulsive disorder patients (n=57) taking
immediate-release fluvoxamine maleate than in patients taking placebo (Prod Info LUVOX(R) oral
tablets, 2007).
c) SSRIs reduce uptake of serotonin by platelets; therefore, reduction in granular storage of serotonin
is observed. Serotonin-mediated platelet aggregation may be decreased. For minor bleeding diatheses
(ie, bruising), treatment is usually unnecessary because it usually resolves with continued treatment.
However, if bleeding is clinically significant, occurs with other underlying medical illnesses, or fails to
improve with time, the drug should be discontinued. Many cases of bleeding have occurred in patients
taking doses at the higher end of the dose range. Bleeding is more common in patients with underlying
diseases; 1 case occurred in a patient with HIV (Berk & Jacobson, 1998).
d) A 33-year-old woman began taking paroxetine 40 mg daily for panic attacks and noted spontaneous
bruising on her arms and legs and excessive menstrual bleeding within 2 weeks. No gynecologic or
hematologic abnormalities were identified. Vitamin C added to paroxetine stopped bleeding in 3 weeks;
discontinuation of vitamin C resulted in recurrent bleeding. Her medication was switched to fluvoxamine
which also caused bleeding that resolved with vitamin C (Tielens, 1997).
3.3.6 Hepatic Effects
3.3.6.A Fluvoxamine Maleate
3.3.6.A.1 Liver function tests abnormal
a) Incidence: extended-release, 2% (Prod Info LUVOX(R) CR extended-release oral capsules, 2008)
b) In 2 short-term, placebo-controlled clinical trials evaluating extended-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of social anxiety disorder, abnormal results of liver
function tests were reported in 2% of fluvoxamine maleate patients (n=279) compared with less than 1%
of placebo patients (n=276) (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
c) A 57-year-old man experienced a 3-fold increase in gamma glutamyl transferase (GGT) of 176
international units/L over baseline (50 international units/L) after 3 weeks of fluvoxamine maleate 100
mg twice daily. An enlarged liver with evidence of fatty changes was observed on abdominal ultrasound
and examination. GGT levels returned to near baseline levels 5 weeks after discontinuing therapy
(Green, 1988).
3.3.7 Immunologic Effects
3.3.7.A Fluvoxamine Maleate
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 16
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
17 of 160
Page 17
of 244
3.3.7.A.1 Stevens-Johnson syndrome
a) Stevens-Johnson syndrome has been reported during postmarketing use of immediate-release
fluvoxamine maleate, although a causal relationship has not been established (Prod Info LUVOX(R)
oral tablets, 2007; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3.3.8 Musculoskeletal Effects
3.3.8.A Fluvoxamine Maleate
Fracture of bone
Fracture of bone, Nonvertebral
Leg cramp
Myalgia
3.3.8.A.1 Fracture of bone
a) Incidence: less than 0.1% (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info
LUVOX(R) oral tablets, 2007)
b) Pathological fracture was reported in less than 0.1% of patients with major depressive disorder or
obsessive-compulsive disorder who took immediate-release fluvoxamine maleate during premarketing
clinical trials (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral
tablets, 2007).
c) In a population-based, randomized, prospective cohort study adjusted for potential covariates, an
increased risk of fragility fracture was reported at the 5-year follow-up in patients 50 years of age and
older who used daily SSRIs (n=137; mean age of 65.1 years), including fluvoxamine, compared with
those who did not use an SSRI (n=4871; mean age of 65.7 years). Daily SSRI use was associated with
a significant 2.1-fold increased risk of fragility fracture (95% confidence interval (CI), 1.3 to 3.4). Daily
SSRI users who were recurrent (ie, treated with SSRIs at baseline and at 5-year follow-up) had a
significant 2.1-fold increased risk of fragility fracture (95% CI, 1.1 to 4.0). Fractures were reported at the
following sites: forearm (40%), ankle and foot (21%), hip (13%), rib (13%), femur (9%), and back (4%).
None were reported at the skull, toes, or fingers (Richards et al, 2007).
3.3.8.A.2 Fracture of bone, Nonvertebral
a) In a prospective, population-based, cohort study (n=7983) with a mean follow-up of 8.4 years, there
was an increased risk of nonvertebral fracture in adult participants older than 55 years of age (mean
age of 77.5 years) who were currently using an SSRI (citalopram, escitalopram, fluoxetine, fluvoxamine,
paroxetine, or sertraline) compared to those who were not exposed to antidepressants. Current SSRI
use was associated with an increased risk of nonvertebral fracture (adjusted hazard ratio (HR), 2.35;
95% confidence interval (CI), 1.32 to 4.18) compared with no antidepressant use. Current SSRI use
was also associated with an increased risk of nonvertebral fracture (adjusted HR, 2.07; 95% CI, 1.23 to
3.5) compared with past antidepressant use (n=1217). In addition, duration of SSRI use showed a 9%
increase in fracture risk per extra month on an SSRI (95% CI, 3% to 16%; p for trend=0.004). Fractures
of the hip (most frequent), wrist, humerus, and pelvis were reported (Ziere et al, 2008).
3.3.8.A.3 Leg cramp
a) There was a two-fold increase in the rate of leg cramps in studies of obsessive-compulsive disorder
(OCD) treatment compared with studies of OCD and depression (Prod Info LUVOX(R) oral tablets,
2007).
3.3.8.A.4 Myalgia
a) Incidence: extended-release (obsessive-compulsive disorder), 5% (Prod Info LUVOX(R) CR
extended-release oral capsules, 2008)
b) The use of 100 mg/day to 300 mg/day extended-release fluvoxamine maleate has been evaluated in
short-term, placebo-controlled trials of social anxiety disorder (SAD) and obsessive-compulsive disorder
(OCD). For use in OCD treatment, 5% of fluvoxamine maleate patients (n=124) reported myalgia
compared with 2% of placebo patients (n=124). Myalgia was not reported during SAD treatment (Prod
Info LUVOX(R) CR extended-release oral capsules, 2008). In short-term, placebo-controlled clinical
trials evaluating immediate-release fluvoxamine maleate (100 mg/day to 300 mg/day) for the treatment
of OCD, myalgia was reported at a rate that was two-fold higher than the rate reported in OCD and
depression trials (Prod Info LUVOX(R) oral tablets, 2007).
3.3.9 Neurologic Effects
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 17
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
18 of 160
Page 18
of 244
Fluvoxamine
Fluvoxamine Maleate
3.3.9.A Fluvoxamine
3.3.9.A.1 Seizure
See Drug Consult reference: COMPARATIVE INCIDENCE OF SEIZURES FROM
ANTIDEPRESSANTS
3.3.9.B Fluvoxamine Maleate
Asthenia
Dizziness
EEG abnormality
Extrapyramidal disease
Headache
Hyperactive behavior
Insomnia
Myoclonus
Seizure
Serotonin syndrome
Sleep disorder
Somnolence
Tremor
3.3.9.B.1 Asthenia
a) Incidence: immediate-release, 14%; extended-release (social anxiety disorder), 24%; extendedrelease (obsessive-compulsive disorder), 26% (Prod Info LUVOX(R) CR extended-release oral
capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
asthenia was reported in 14% of fluvoxamine maleate patients (n=892) compared with 6% of placebo
patients (n=778). There was a two-fold increase in the rate of asthenia in studies of OCD treatment
compared with studies of OCD and depression (Prod Info LUVOX(R) oral tablets, 2007). The use of 100
mg/day to 300 mg/day extended-release fluvoxamine maleate has been evaluated in short-term,
placebo-controlled trials of social anxiety disorder (SAD) and OCD. For use in SAD treatment, 24% of
fluvoxamine maleate patients (n=279) reported asthenia compared with 10% of placebo patients
(n=276). For use in OCD treatment, 26% of fluvoxamine maleate patients (n=124) reported asthenia
compared with 8% of placebo patients (n=124) (Prod Info LUVOX(R) CR extended-release oral
capsules, 2008).
3.3.9.B.2 Dizziness
a) Incidence: immediate-release, 11%; extended-release (social anxiety disorder), 15%; extendedrelease (obsessive-compulsive disorder), 12% (Prod Info LUVOX(R) CR extended-release oral
capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 18
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
19 of 160
Page 19
of 244
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
dizziness was reported in 11% of fluvoxamine maleate patients (n=892) compared with 6% of placebo
patients (n=778) (Prod Info LUVOX(R) oral tablets, 2007). The use of 100 mg/day to 300 mg/day
extended-release fluvoxamine maleate has been evaluated in short-term, placebo-controlled trials of
social anxiety disorder (SAD) and OCD. For use in SAD treatment, 15% of fluvoxamine maleate
patients (n=279) reported dizziness compared with 7% of placebo patients (n=276). For use in OCD
treatment, 12% of fluvoxamine maleate patients (n=124) reported dizziness compared with 10% of
placebo patients (n=124) (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
c) Event monitoring in Great Britain of fluvoxamine use in 10,401 patients revealed the most common
category of adverse events to be neuropsychiatric. Dizziness was reported in 3.3% of patients (Edwards
et al, 1994).
d) In an open study of more than 5000 patients with depression, dizziness was reported by 4.5% of
patients (Martin et al, 1987).
e) Dizziness was reported in 14% of patients who received fluvoxamine (n=222) during 10 double-blind,
placebo-controlled studies comparing fluvoxamine and imipramine in patients with depression (Benfield
& Ward, 1986b).
3.3.9.B.3 EEG abnormality
a) EEG profiles of patients being treated with fluvoxamine showed concomitant increases of slow and
fast activities and a decrease in alpha activity indicating sedative qualities. Single doses of fluvoxamine
75 mg were administered to 10 healthy volunteers. The EEG studies showed that fluvoxamine induced
less augmentation of slow activity than imipramine, indicating fewer sedative properties with
fluvoxamine (Saletu et al, 1983).
3.3.9.B.4 Extrapyramidal disease
a) Incidence: 0.1% to 1% (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info
LUVOX(R) oral tablets, 2007)
b) Extrapyramidal syndrome was reported in 0.1% to 1% of patients with major depressive disorder or
obsessive-compulsive disorder who took immediate-release fluvoxamine maleate during premarketing
clinical trials (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral
tablets, 2007).
c) Dystonic reactions, parkinsonism, akathisia, and dyskinesias have been described, with the earliest
onset noted at 5 days (Bronner & Vanneste, 1998) and latest onset at 4 months (Chong, 1995).
d) Extrapyramidal reactions (EPR) have been reported with 1 or more SSRIs. The majority of case
reports involved fluoxetine; however, all of the SSRIs were implicated in at least 1 EPR. Duration of
symptoms with treatment was usually a few days. Symptoms occurred weekly for the first 4 weeks of
treatment and periodically thereafter. For most cases, treatment was limited to reducing the dose or
stopping the SSRI (Caley, 1997; Gill et al, 1997).
e) In a limited number of case reports, propranolol and/or benzodiazepines were used to treat SSRIinduced akathisia; the dose of propranolol ranged from 40 to 90 mg daily (Gill et al, 1997).
f) In case reports, dystonic reactions responded to an unspecified dose of intramuscular
trihexyphenidyl or diphenhydramine 50 mg (Gill et al, 1997; George & Trimble, 1993).
g) Possible mechanisms by which SSRIs cause extrapyramidal reactions (EPR) include: (1) central
serotonergic activity which inhibits dopaminergic activity; and (2) concurrent use of an SSRI and
antipsychotic may cause EPRs by a pharmacokinetic interaction, a pharmacodynamic interaction, or a
combination of the two (Caley, 1997).
h) Three days after starting concomitant fluvoxamine and metoclopramide, a 14-year-old boy
developed acute dystonia of the extensor muscles of the neck, back, and upper extremities; jaw rigidity;
horizontal nystagmus; dysarthria; and uncontrolled movement of the tongue. He was treated with
fluvoxamine 50 mg/day and metoclopramide 10 mg 3 times daily. Treatment with intramuscular
biperiden 5 mg completely relieved symptoms within 30 minutes. Previous treatment with
metoclopramide did NOT produce dystonia (Palop et al, 1999).
i) A 71-year-old woman developed involuntary movements of the head, neck, and extremities,
especially the arms, 5 days after she began taking fluvoxamine 50 mg daily for depression. Upon
examination in the emergency department, the movements occurred at rest and were NOT
suppressible; they were described as dystonic contractures and myoclonic jerks. Treatment consisted of
IV clonazepam 1 mg which resulted in improvement within 10 minutes; 2 hours later, myoclonus
recurred and responded to oral clonazepam 2 mg. Fluvoxamine was stopped and myoclonus resolved.
One week later, this woman was rechallenged with fluvoxamine 50 mg daily which resulted in a similar
reaction 11 days later. The abnormal movements resolved after administering oral clonazepam 2 mg.
After stopping fluvoxamine, the movements disappeared and did NOT recur during 6 months of followup. Of note, this woman was also taking diltiazem, which inhibits the cytochrome P450 enzyme 1A2 (the
enzyme responsible for metabolizing fluvoxamine). This may have resulted in increased fluvoxamine
bioavailability (Bronner & Vanneste, 1998).
j) About 4 months after starting fluvoxamine 100 mg daily, a 38-year-old woman complained of
periauricular pain and headache which progressed to tightening of jaw muscles and teeth clenching
over the next month. She also had difficulty chewing solid foods. Upon reduction of the fluvoxamine
dose to 50 mg, her complaints lessened but did NOT completely resolve until she stopped fluvoxamine.
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 19
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
20 of 160
Page 20
of 244
This patient did NOT have a history of previous psychiatric illnesses or dystonias (Chong, 1995).
3.3.9.B.5 Headache
a) Incidence: immediate-release, 22%; extended-release (social anxiety disorder), 35%; extendedrelease (obsessive-compulsive disorder), 32% (Prod Info LUVOX(R) CR extended-release oral
capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
headache was reported in 22% of fluvoxamine maleate patients (n=892) compared with 20% of placebo
patients (n=778) (Prod Info LUVOX(R) oral tablets, 2007). The use of 100 mg/day to 300 mg/day
extended-release fluvoxamine maleate has been evaluated in short-term, placebo-controlled trials of
social anxiety disorder (SAD) and OCD. For use in SAD treatment, 35% of fluvoxamine maleate
patients (n=279) reported headache compared with 30% of placebo patients (n=276). For use in OCD
treatment, 32% of fluvoxamine maleate patients (n=124) reported headache compared with 31% of
placebo patients (n=124) (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
c) Event monitoring in Great Britain of fluvoxamine use in 10,401 patients revealed the most common
category of adverse events to be neuropsychiatric. Headache was reported in 3.9% of patients
(Edwards et al, 1994).
d) In an open study of more than 5000 patients with depression, headache was reported by 5% of
patients, causing withdrawal from the study in 2.7% (Martin et al, 1987).
e) Headache was reported in 22% of patients who received fluvoxamine (n=222) during 10 doubleblind, placebo-controlled studies comparing fluvoxamine and imipramine in patients with depression
(Benfield & Ward, 1986b).
3.3.9.B.6 Hyperactive behavior
a) In a placebo-controlled study involving pediatric patients with obsessive-compulsive disorder,
hyperkinesia was reported in 5% or more of patients treated with immediate-release fluvoxamine
maleate. This was at least twice the rate found in placebo-treated patients (Prod Info LUVOX(R) oral
tablets, 2007).
3.3.9.B.7 Insomnia
a) Incidence: immediate-release, 21%; extended-release (social anxiety disorder), 32%; extendedrelease (obsessive-compulsive disorder), 35% (Prod Info LUVOX(R) CR extended-release oral
capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
insomnia was reported in 21% of fluvoxamine maleate patients (n=892) compared with 10% of placebo
patients (n=778) (Prod Info LUVOX(R) oral tablets, 2007). The use of 100 mg/day to 300 mg/day
extended-release fluvoxamine maleate has been evaluated in short-term, placebo-controlled trials of
social anxiety disorder (SAD) and OCD. For use in SAD treatment, 32% of fluvoxamine maleate
patients (n=279) reported insomnia compared with 13% of placebo patients (n=276). For use in OCD
treatment, 35% of fluvoxamine maleate patients (n=124) reported insomnia compared with 20% of
placebo patients (n=124) (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
c) Event monitoring in Great Britain of fluvoxamine use in 10,401 patients revealed the most common
category of adverse events to be neuropsychiatric. Insomnia was reported in 2.4% of patients (Edwards
et al, 1994).
d) Insomnia was reported in 15% of patients who received fluvoxamine (n=222) during 10 double-blind,
placebo-controlled studies comparing fluvoxamine and imipramine in patients with depression (Benfield
& Ward, 1986b).
3.3.9.B.8 Myoclonus
a) There was a two-fold increase in the rate of myoclonus/twitch in studies of obsessive-compulsive
disorder (OCD) treatment compared with studies of OCD and depression. Myoclonus was reported in at
least 1% and twitching was reported in 0.1% to 1% of patients with major depressive disorder or OCD
who took immediate-release fluvoxamine maleate during premarketing clinical trials (Prod Info LUVOX
(R) oral tablets, 2007). Twitching was reported in 2% of patients with OCD who were treated with
fluvoxamine maleate extended-release 100 mg/day to 300 mg/day (n=124) compared with 0% of
placebo-treated patients (n=124) during short-term, placebo-controlled trials of social anxiety disorder
(SAD) and OCD. Twitching was not reported in patients with SAD (Prod Info LUVOX(R) CR extendedrelease oral capsules, 2008).
b) A 71-year-old woman developed involuntary movements of the head, neck, and extremities,
especially the arms, 5 days after she began taking fluvoxamine 50 mg daily for depression. Upon
examination in the emergency department, the movements occurred at rest and were NOT
suppressible; they were described as dystonic contractures and myoclonic jerks. Treatment consisted of
IV clonazepam 1 mg which resulted in improvement within 10 minutes; 2 hours later, myoclonus
recurred and responded to oral clonazepam 2 mg. Fluvoxamine was stopped and myoclonus resolved.
One week later, this woman was rechallenged with fluvoxamine 50 mg daily which resulted in a similar
reaction 11 days later. The abnormal movements resolved after administering oral clonazepam 2 mg.
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 20
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
21 of 160
Page 21
of 244
After stopping fluvoxamine, the movements disappeared and did NOT recur during 6 months of followup. Of note, this woman was also taking diltiazem, which inhibits the cytochrome P450 enzyme 1A2 (the
enzyme responsible for metabolizing fluvoxamine). This may have resulted in increased fluvoxamine
bioavailability (Bronner & Vanneste, 1998).
3.3.9.B.9 Seizure
a) Incidence: 0.2% (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX
(R) oral tablets, 2007)
b) Seizures occurred in 0.2% of patients treated with immediate-release fluvoxamine maleate during
premarketing trials. Cautious administration is recommended in patients with controlled epilepsy or a
history of convulsions. Avoid treatment in unstable epilepsy. Discontinue fluvoxamine maleate if
seizures occur or increase in frequency (Prod Info LUVOX(R) CR extended-release oral capsules,
2008; Prod Info LUVOX(R) oral tablets, 2007).
c) A 49-year-old male who had been seizure-free for 10 years with anticonvulsant therapy experienced
a generalized seizure 3 days after beginning fluvoxamine therapy, 150 mg at bedtime. Following an
increase in dose of the anticonvulsant therapy, the patient did not experience any more seizures (Kim et
al, 2000).
3.3.9.B.10 Serotonin syndrome
a) Serotonin syndrome, which may include mental status changes (eg, agitation, hallucination, and
coma), autonomic instability (eg, tachycardia, hyperthermia, and labile blood pressure), neuromuscular
aberrations, and gastrointestinal symptoms (eg, nausea, vomiting, and diarrhea), may occur with
fluvoxamine maleate. This syndrome could be life-threatening. Risk is increased with concomitant use
of SSRIs, serotonin norepinephrine reuptake inhibitors (SNRI), triptans, and MAOIs (contraindicated). If
concomitant use with SSRIs, SNRIs, or a triptan is warranted, increased monitoring is advised (Prod
Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007).
b) A serotonin syndrome has been described with administration of fluvoxamine. Symptoms include
anxiety, coma, confusion, diaphoresis, disorientation, hyperreflexia, hypertension, hyperthermia,
myoclonus, rigidity, seizures, and tremor. Incidence is rare (less than 0.1%). In severe cases,
hospitalization has been required for treatment (Gill et al, 1999).
c) An 11-year-old boy developed serotonin syndrome (SS) 1 hour after receiving fluvoxamine 50 mg for
attention deficit disorder. He was also receiving perphenazine and benztropine, which had been used
for 2 years. Symptoms of SS included agitation, unresponsiveness to verbal or painful stimuli,
fluctuating blood pressure and heart rate, jaw myoclonus, shivering, fever to 103.5 degrees Fahrenheit,
and hyperreflexia with rigidity of the lower extremities. Initial treatment consisted of diazepam 10 mg
and lorazepam 21 mg in incremental intravenous doses. Due to a rise in temperature, he was paralyzed
with rocuronium 50 mg and intubated; sedation and pharmacologic paralysis were continued for 24
hours. Full recovery occurred 48 hours after hospitalization (Gill et al, 1999).
3.3.9.B.11 Sleep disorder
a) Incidence: 0.1% to 1% (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info
LUVOX(R) oral tablets, 2007)
b) Sleep disorder was reported in 0.1% to 1% of patients with major depressive disorder or obsessivecompulsive disorder who took immediate-release fluvoxamine maleate during premarketing clinical trials
(Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets,
2007).
c) Fluvoxamine 100 to 150 mg tended to increase rapid eye movement (REM) sleep latency, increase
stage 3 sleep, and shorten REM time in a placebo-controlled trial of healthy volunteers. The overall
quality of sleep deteriorated, and subjects complained of feeling worse in the mornings (Benfield &
Ward, 1986b).
3.3.9.B.12 Somnolence
a) Incidence: immediate-release, 22%; extended-release (social anxiety disorder), 26%; extendedrelease (obsessive-compulsive disorder), 27% (Prod Info LUVOX(R) CR extended-release oral
capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
somnolence was reported in 22% of fluvoxamine maleate patients (n=892) compared with 8% of
placebo patients (n=778) (Prod Info LUVOX(R) oral tablets, 2007). The use of 100 mg/day to 300
mg/day extended-release fluvoxamine maleate has been evaluated in short-term, placebo-controlled
trials of social anxiety disorder (SAD) and OCD. For use in SAD treatment, 26% of fluvoxamine maleate
patients (n=279) reported somnolence compared with 9% of placebo patients (n=276). For use in OCD
treatment, 27% of fluvoxamine maleate patients (n=124) reported somnolence compared with 11% of
placebo patients (n=124) (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
c) In an open study of more than 5000 patients with depression, somnolence was reported by 3.8% of
patients (Martin et al, 1987).
d) Somnolence was reported in 26% of patients who received fluvoxamine (n=222) during 10 doubleblind, placebo-controlled studies comparing fluvoxamine and imipramine in patients with depression
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 21
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
22 of 160
Page 22
of 244
(Benfield & Ward, 1986b).
3.3.9.B.13 Tremor
a) Incidence: immediate-release, 5%; extended-release (social anxiety disorder), 8%; extended-release
(obsessive-compulsive disorder), 6% (Prod Info LUVOX(R) CR extended-release oral capsules, 2008;
Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
tremor was reported in 5% of fluvoxamine maleate patients (n=892) compared with 1% of placebo
patients (n=778) (Prod Info LUVOX(R) oral tablets, 2007). The use of 100 mg/day to 300 mg/day
extended-release fluvoxamine maleate has been evaluated in short-term, placebo-controlled trials of
social anxiety disorder (SAD) and OCD. For use in SAD treatment, 8% of fluvoxamine maleate patients
(n=279) reported tremor compared with less than 1% of placebo patients (n=276). For use in OCD
treatment, 6% of fluvoxamine maleate patients (n=124) reported tremor compared with 0% of placebo
patients (n=124) (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3.3.10 Ophthalmic Effects
3.3.10.A Fluvoxamine Maleate
Blurred vision
Raised intraocular pressure
3.3.10.A.1 Blurred vision
a) Incidence: immediate-release, 3%; extended-release (obsessive-compulsive disorder), 2%(Prod Info
LUVOX(R) oral tablets, 2007; Prod Info LUVOX(R) CR extended-release oral capsules, 2008)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
amblyopia (mostly "blurred vision") was reported in 3% of fluvoxamine maleate patients (n=892)
compared with 2% of placebo patients (n=778). There was a two-fold decrease in the rate of amblyopia
(mostly "blurred vision") in studies of OCD treatment compared with studies of OCD and depression
(Prod Info LUVOX(R) oral tablets, 2007). Amblyopia was reported in 2% of patients with OCD who were
treated with fluvoxamine maleate (n=124) compared with less than 1% of placebo-treated patients
(n=124) during short-term, placebo-controlled trials of social anxiety disorder (SAD) and OCD.
Amblyopia was not reported in patients with SAD (Prod Info LUVOX(R) oral tablets, 2007).
3.3.10.A.2 Raised intraocular pressure
a) Aggravation of glaucoma and mydriasis in one patient was attributed to fluvoxamine given to treat
tension headache. A 66-year-old woman who was being treated with timolol 0.25% twice per day for
narrow-angle glaucoma developed severe orbital pain and blurred vision 2 months after initiation of
treatment with fluvoxamine 50 mg/day for tension headache and depression. The headache and mood
disorder improved with fluvoxamine. However, she was found to have increased ocular pressure,
mydriasis, and a closed angle. The eye problems were treated with intravenous glycerol 50%,
acetazolamide 1.5 mg/kg, and pilocarpine 2% 4 applications/day for 1 day. The usual dose of timolol
was continued. Intraocular pressure was reduced by the treatment but rose again after 3 days.
Discontinuation of fluvoxamine resulted in normalization of intraocular pressure and resolution of orbital
pain and blurred vision within 2 days (Jimenez-Jimenez et al, 2001).
3.3.12 Psychiatric Effects
3.3.12.A Fluvoxamine Maleate
Agitation
Anxiety
Depression, worsening
Feeling nervous
Frontal lobe syndrome
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 22
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
23 of 160
Page 23
of 244
Hypomania
Mania
Psychiatric sign or symptom
Psychotic disorder
Suicidal thoughts
3.3.12.A.1 Agitation
a) Incidence: immediate-release, 2%; extended-release (social anxiety disorder), 3%; extended-release
(obsessive-compulsive disorder), 2% (Prod Info LUVOX(R) oral tablets, 2007; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
agitation was reported in 2% of fluvoxamine maleate patients (n=892) compared with 1% of placebo
patients (n=778). There was a two-fold increase in the rate of agitation in studies of OCD treatment
compared with studies of OCD and depression(Prod Info LUVOX(R) oral tablets, 2007). The use of 100
mg/day to 300 mg/day extended-release fluvoxamine maleate has been evaluated in short-term,
placebo-controlled trials of social anxiety disorder (SAD) and OCD. For use in SAD treatment, 3% of
fluvoxamine maleate patients (n=279) reported agitation compared with less than 1% of placebo
patients (n=276). For use in OCD treatment, 2% of fluvoxamine maleate patients (n=124) reported
agitation compared with less than 1% of placebo patients (n=124) (Prod Info LUVOX(R) CR extendedrelease oral capsules, 2008).
c) Severe agitation was reported in an 11-year-old boy following the ingestion of one therapeutic (50
mg) fluvoxamine tablet (Gill et al, 1999).
d) A 68-year-old male experienced severe agitation and restlessness within one week of beginning
fluvoxamine therapy, 50 mg daily. The akathisia began to subside gradually following discontinuation of
the fluvoxamine and administration of diazepam (Chong & Cheong, 1999).
e) Agitation was noted in 16% of patients taking fluvoxamine therapeutically (Benfield & Ward, 1986b).
3.3.12.A.2 Anxiety
a) Incidence: immediate-release, 5%; extended-release (social anxiety disorder), 8%; extended-release
(obsessive-compulsive disorder), 6% (Prod Info LUVOX(R) CR extended-release oral capsules, 2008;
Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
anxiety was reported in 5% of fluvoxamine maleate patients (n=892) compared with 3% of placebo
patients (n=778). There was a two-fold increase in the rate of anxiety in studies of OCD treatment
compared with studies of OCD and depression(Prod Info LUVOX(R) oral tablets, 2007). The use of 100
mg/day to 300 mg/day extended-release fluvoxamine maleate has been evaluated in short-term,
placebo-controlled trials of social anxiety disorder (SAD) and OCD. For use in SAD treatment, 8% of
fluvoxamine maleate patients (n=279) reported anxiety compared with 5% of placebo patients (n=276).
For use in OCD treatment, 6% of fluvoxamine maleate patients (n=124) reported anxiety compared with
2% of placebo patients (n=124) (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
c) Event monitoring in Great Britain of fluvoxamine use in 10,401 patients revealed the most common
category of adverse events to be neuropsychiatric. Anxiety was reported in 2.6% of patients (Edwards
et al, 1994).
3.3.12.A.3 Depression, worsening
a) Adult and pediatric patients being treated with antidepressants for major depressive disorder who
experience symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness,
impulsivity, akathisia (psychomotor restlessness), hypomania, or mania may be at risk of suicidal
ideation and behavior (suicidality). This same concern applies to patients being treated for other
psychiatric and nonpsychiatric disorders. If these symptoms are observed, therapy should be reevaluated, and it may be necessary to discontinue medications when symptoms are severe, sudden in
onset, or were not part of the patient's initial symptoms. The dose should be tapered off, avoiding abrupt
discontinuation whenever possible. Patients and their caregivers should be provided with the
Medication Guide that is available for this drug (Prod Info LUVOX(R) CR extended-release oral
capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007; Anon, 2004).
3.3.12.A.4 Feeling nervous
a) Incidence: immediate-release, 12%; extended-release (social anxiety disorder), 10% (Prod Info
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 23
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
24 of 160
Page 24
of 244
LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
nervousness was reported in 12% of fluvoxamine maleate patients (n=892) compared with 5% of
placebo patients (n=778) (Prod Info LUVOX(R) oral tablets, 2007). The use of 100 mg/day to 300
mg/day extended-release fluvoxamine maleate has been evaluated in short-term, placebo-controlled
trials of social anxiety disorder (SAD) and OCD. For use in SAD treatment, 10% of fluvoxamine maleate
patients (n=279) reported nervousness compared with 9% of placebo patients (n=276). Nervousness
was not reported as an adverse effect in OCD treatment (Prod Info LUVOX(R) CR extended-release
oral capsules, 2008).
3.3.12.A.5 Frontal lobe syndrome
a) A patient developed a frontal lobe syndrome (apathy, indifference) while taking moderate doses of
fluvoxamine 150 mg/day and sulpiride, a dopamine (D-2) antagonist, at 400 mg/day. It was theorized
that serotonergic agents may cause this syndrome via reduction of frontal blood flow and that
dopamine-blocking agents may modulate this effect (George & Trimble, 1992).
b) Apathy, indifference, loss of initiative, and disinhibition were reported in association with fluvoxamine
treatment of 2 patients with panic disorder. The effects appeared to be dose-related and disappeared
rapidly when the dose of fluvoxamine, which has a short elimination half-life, was reduced. Patients'
behavior seemed to resemble that of people with frontal lobe dysfunction (Hoehn-Saric et al, 1990).
3.3.12.A.6 Hypomania
a) Incidence: 1% (Prod Info LUVOX(R) oral tablets, 2007; Prod Info LUVOX(R) CR extended-release
oral capsules, 2008)
b) Mania or hypomania was reported in 1% of patients with primarily depression who took fluvoxamine
maleate during premarketing clinical trials (Prod Info LUVOX(R) oral tablets, 2007; Prod Info LUVOX(R)
CR extended-release oral capsules, 2008).
c) During an 8-week, placebo-controlled study of fluvoxamine for obsessive-compulsive disorder
(OCD), 5 of 20 patients became manic (2) or hypomanic (3). This is inconsistent with prior experience
with other serotonin re-uptake inhibitors. The rate of hypomania associated with fluvoxamine when
treating major depression is 0.4%, that for clomipramine when treating OCD is 0.4%, and that for
fluoxetine in the treatment of depression is 0.98%. The high percentage (25%) in this study may reflect
the presence of bipolar type II patients in the sample as these patients show a greater frequency of
cycling (Jefferson et al, 1991).
3.3.12.A.7 Mania
a) Incidence: 1% to 4% (Prod Info LUVOX(R) oral tablets, 2007; Prod Info LUVOX(R) CR extendedrelease oral capsules, 2008)
b) Mania or hypomania was reported in 1% of patients with primarily depression who took fluvoxamine
maleate during premarketing clinical trials. Manic reactions were reported in 4% of pediatric patients
with obsessive-compulsive disorder who were given fluvoxamine maleate (n=57) during a ten-week
study, compared with no manic reactions in patients who received placebo (n=63). Caution is advised
when fluvoxamine maleate is used in patients with a history of mania (Prod Info LUVOX(R) oral tablets,
2007; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
c) Mania occurred in 3 patients who were treated with a combination of fluvoxamine and lithium.
Dosage of fluvoxamine was 100 to 200 mg/day and lithium levels were low, ie, 0.5, 0.55, 0.6 mmol/L.
This may represent a "switch" from depression into mania induced by fluvoxamine (Burrai et al, 1991c).
d) During an 8-week, placebo-controlled study of fluvoxamine for obsessive-compulsive disorder
(OCD), 5 of 20 patients became manic (2) or hypomanic (3). This is inconsistent with prior experience
with other serotonin re-uptake inhibitors. The rate of hypomania associated with fluvoxamine when
treating major depression is 0.4%, that for clomipramine when treating OCD is 0.4%, and that for
fluoxetine in the treatment of depression is 0.98%. The high percentage (25%) in this study may reflect
the presence of bipolar type II patients in the sample as these patients show a greater frequency of
cycling (Jefferson et al, 1991).
3.3.12.A.8 Psychiatric sign or symptom
a) Behavioral and mood changes (such as motor activation, impulsivity, aggression, and dysphoria)
were observed in 5 patients treated with fluvoxamine (200 to 300 mg/day) for obsessive-compulsive
disorders. The authors recommended reduction, but not discontinuation, of fluvoxamine, with addition of
carbamazepine (Diaferia et al, 1994).
3.3.12.A.9 Psychotic disorder
a) Incidence: at least 1% (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info
LUVOX(R) oral tablets, 2007)
b) Psychotic reaction was reported in at least 1% of patients with major depressive disorder or
obsessive-compulsive disorder who took immediate-release fluvoxamine maleate during premarketing
clinical trials (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral
tablets, 2007).
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 24
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
25 of 160
Page 25
of 244
c) Acute exacerbation of schizophrenic symptoms (hallucinations, attacks of anger) occurred in a 53year-old woman with chronic schizophrenia since age 30 when fluvoxamine 150 mg/day was added to
her treatment program for depression. After discontinuation of fluvoxamine and increase of
perphenazine (from 16 to 32 mg/day), the patient was free of psychotic symptoms (Rocco & De Leo,
1992).
d) A 17-year-old male with mild mental retardation experienced an acute psychotic reaction resulting in
hospitalization for 6 days following a single dose of fluvoxamine 50 mg for depression and anxiety
symptoms. The subject experienced agitation, insomnia, auditory and visual hallucinations, fearful
mood, paranoid delusions, and episodes of catatonia within 24 hours of taking fluvoxamine. Forty-eight
hours after the fluvoxamine dose the subject was hospitalized with an unremarkable physical
examination, negative drug screen, and normal laboratories. He was treated with haloperidol 2 mg,
lorazepam 1 mg, and chlorpromazine 50 mg. Psychotic symptoms improved within 72 hours of
admission and after an additional 72 hours of observation, the subject was discharged on no
medication. Medical history was negative for past psychotic presentations and substance abuse history
(Sim & Massabki, 2000).
3.3.12.A.10 Suicidal thoughts
a) Adult and pediatric patients being treated with antidepressants for major depressive disorder who
experience symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness,
impulsivity, akathisia (psychomotor restlessness), hypomania, or mania may be at risk of suicidal
ideation and behavior (suicidality). This same concern applies to patients being treated for other
psychiatric and nonpsychiatric disorders. If these symptoms are observed, therapy should be reevaluated, and it may be necessary to discontinue medications when symptoms are severe, sudden in
onset, or were not part of the patient's initial symptoms. The dose should be tapered off, avoiding abrupt
discontinuation whenever possible. Patients and their caregivers should be provided with the
Medication Guide that is available for this drug (Prod Info LUVOX(R) CR extended-release oral
capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007; Anon, 2004; Anon, 2004).
b) A causal role for antidepressants in inducing suicidality has been established in children,
adolescents, and young adults (up to 24 years old). Anyone considering the use of antidepressants in a
child, adolescent, or young adult must balance this risk with the clinical need. Families and caregivers
should be encouraged to observe the patient carefully for emerging symptoms and unexpected
behavior. This causal role in children and adolescents was determined from pooled analyses of 24
short-term, placebo-controlled trials of 9 antidepressants (SSRIs and others) which included over 4400
patients with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric
disorders. The causal role in adults was determined from pooled analyses of 295 short-term, placebocontrolled trials of 11 antidepressants which included over 77,000 patients with major depressive
disorder or other psychiatric disorders. The risk of suicidal thinking and behavior was increased in
children, adolescents, and young adults up to 24 years old. This increased risk did not exist in adults
over 24 years old, and the risk was lower in adults over 65 years old. The risk was highest in patients
with major depressive disorder, but there were signs of risk emerging from trials in other psychiatric
indications, such as OCD and social anxiety disorder. No suicides occurred in the pediatric trials. The
risk of suicidality during longer-term use (ie, beyond several months) is not known (Prod Info LUVOX(R)
CR extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007; Anon, 2004).
3.3.13 Renal Effects
3.3.13.A Fluvoxamine Maleate
3.3.13.A.1 Urinary retention
a) Incidence: immediate-release, 1% (Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
urinary retention was reported in 1% of fluvoxamine maleate patients (n=892) compared with 0% of
placebo patients (n=778). There was a two-fold increase in the rate of urinary retention in studies of
OCD treatment compared with studies of OCD and depression (Prod Info LUVOX(R) oral tablets, 2007).
3.3.14 Reproductive Effects
Fluvoxamine
Fluvoxamine Maleate
3.3.14.A Fluvoxamine
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 25
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
26 of 160
Page 26
of 244
3.3.14.A.1 Sexual dysfunction
See Drug Consult reference: DRUG-INDUCED SEXUAL DYSFUNCTION
See Drug Consult reference: SELECTIVE SEROTONIN REUPTAKE INHIBITOR-INDUCED SEXUAL
DYSFUNCTION
3.3.14.B Fluvoxamine Maleate
Abnormal ejaculation
Amenorrhea
Dysmenorrhea
Impotence
Increased libido
Orgasm incapacity
Priapism
Reduced libido
Sexual dysfunction
3.3.14.B.1 Abnormal ejaculation
a) Incidence: immediate-release, 8%; extended-release (social anxiety disorder), 11%; extendedrelease (obsessive-compulsive disorder), 10% (Prod Info LUVOX(R) oral tablets, 2007; Prod Info
LUVOX(R) CR extended-release oral capsules, 2008)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
abnormal ejaculation (mostly delayed ejaculation) was reported in 8% of male fluvoxamine maleate
patients compared with 1% of placebo patients. There was a two-fold increase in the rate of abnormal
ejaculation (mostly delayed ejaculation) in studies of OCD treatment compared with studies of OCD and
depression(Prod Info LUVOX(R) oral tablets, 2007). The use of 100 mg/day to 300 mg/day extendedrelease fluvoxamine maleate has been evaluated in short-term, placebo-controlled trials of social
anxiety disorder (SAD) and OCD. For use in SAD treatment, 11% of male fluvoxamine maleate patients
reported abnormal ejaculation compared with 2% of placebo patients (n=276). For use in OCD
treatment, 10% of male fluvoxamine maleate patients reported abnormal ejaculation compared with 0%
of placebo patients (n=124) (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
c) Cyproheptadine, 1 mg per 25 mg of fluvoxamine taken 2 hours prior to intercourse was effective in
reversing ejaculatory failure secondary to fluvoxamine in a 63-year-old man with recurrent unipolar
depression. Eventually, 150 mg fluvoxamine per day was effective in controlling the patient's affective
symptoms and 6 mg of cyproheptadine was effective in preventing ejaculatory failure (Arnatt & Nutt,
1994).
3.3.14.B.2 Amenorrhea
a) Amenorrhea has been listed in postmarketing reports of immediate-release fluvoxamine maleate
use, although a causal relationship has not been established (Prod Info LUVOX(R) CR extendedrelease oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007).
b) Galactorrhea and amenorrhea associated with fluvoxamine were reported in a 38-year-old woman
with refractory bipolar affective disorder; this patient had been treated for over a decade with several
psychotropic agents. The patient had been maintained for an undetermined length of time on loxapine
150 mg daily, oxazepam 30 mg three times daily, and zopiclone 7.5 mg at bedtime. Fluvoxamine was
prescribed for depression, and the dose was titrated to 150 mg daily while the loxapine dosage was
decreased to 75 mg daily. Six weeks after starting fluvoxamine, she complained of amenorrhea followed
soon by galactorrhea. Thorough evaluation ruled out an underlying organic etiology; however, the
serum prolactin level was 80 mcg/L (normal, 4 to 30 mcg/L). Galactorrhea resolved 3 weeks after
stopping fluvoxamine, and menstruation resumed a week later. The temporal relationship between
fluvoxamine and the onset of galactorrhea and amenorrhea suggests a possible etiologic role for
fluvoxamine (Jeffries et al, 1992).
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 26
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
27 of 160
Page 27
of 244
3.3.14.B.3 Dysmenorrhea
a) In a placebo-controlled study involving pediatric patients with obsessive-compulsive disorder,
dysmenorrhea was reported in 5% or more of patients treated with immediate-release fluvoxamine
maleate. This was at least twice the rate found in placebo-treated patients (Prod Info LUVOX(R) oral
tablets, 2007).
3.3.14.B.4 Impotence
a) Incidence: immediate-release, 2% (Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
impotence was reported in 2% of male fluvoxamine maleate patients compared with 1% of male
placebo patients. There was a two-fold increase in the rate of impotence in studies of OCD treatment
compared with studies of OCD and depression (Prod Info LUVOX(R) oral tablets, 2007). Impotence was
reported in 2% of males treated with extended-release fluvoxamine maleate (n=403) compared with 3%
of males treated with placebo (n=400) in trials of social anxiety disorder and OCD treatment (Prod Info
LUVOX(R) CR extended-release oral capsules, 2008).
3.3.14.B.5 Increased libido
a) A 65-year-old female experienced increased sexual desire after 1 week of treatment with
fluvoxamine 25 mg twice daily, medazepam 5 mg twice daily, and flunitrazepam 2 mg once daily for the
treatment of depression and insomnia. Her depressive symptoms dramatically improved; however,
sexual desire increased daily over the second week of therapy. Fluvoxamine was discontinued and
treatment with sulpiride 100 mg twice daily, amoxapine 10 mg twice daily, medazepam 5 mg twice daily,
and flunitrazepam 2 mg once daily were initiated. Symptoms of increased sexual desire disappeared
and did not recur. The subject's past sexual history included cessation of her sexual relationship with
her husband for 10 years prior to this event (Okada & Ikajima, 2000).
3.3.14.B.6 Orgasm incapacity
a) Incidence: immediate-release, 2%; extended-release, 5% (Prod Info LUVOX(R) oral tablets, 2007;
Prod Info LUVOX(R) CR extended-release oral capsules, 2008)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
anorgasmia was reported in 2% of fluvoxamine maleate patients (n=892) compared with 0% of placebo
patients (n=778). There was a two-fold increase in the rate of anorgasmia (in males) in studies of OCD
treatment compared with studies of OCD and depression(Prod Info LUVOX(R) oral tablets, 2007). The
use of 100 mg/day to 300 mg/day extended-release fluvoxamine maleate has been evaluated in shortterm, placebo-controlled trials of social anxiety disorder (SAD) and OCD. For use in SAD treatment, 5%
of fluvoxamine maleate patients (n=279) reported anorgasmia compared with 1% of placebo patients
(n=276). For use in OCD treatment, 5% of fluvoxamine maleate patients (n=124) reported anorgasmia
compared with 0% of placebo patients (n=124) (Prod Info LUVOX(R) CR extended-release oral
capsules, 2008).
c) A 22-year-old woman who had been taking fluvoxamine for 2 months experienced anorgasmia which
was unresponsive to treatment with cyproheptadine 8 and 12 mg; therefore, a reduction in fluvoxamine
dosage was tried. Decreasing the weekend dose to 150 or 200 mg did NOT result in normal sexual
function; a reduction in dose to fluvoxamine 200 mg daily resulted in a return of obsessive symptoms. In
this patient, a partial drug holiday resulted in normal sexual function (Nemeth et al, 1996).
3.3.14.B.7 Priapism
a) Incidence: immediate release, 2% (Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
priapism was reported in 2% of fluvoxamine maleate patients (n=892) compared with 1% of placebo
patients (n=778) (Prod Info LUVOX(R) oral tablets, 2007).
3.3.14.B.8 Reduced libido
a) Incidence: immediate-release, 2%; extended-release (social anxiety disorder), 6%; extended-release
(obsessive-compulsive disorder), 6% (Prod Info LUVOX(R) CR extended-release oral capsules, 2008;
Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
decreased libido was reported in 2% of fluvoxamine maleate patients (n=892) compared with 1% of
placebo patients (n=778). There was a two-fold increase in the rate of decreased libido in studies of
OCD treatment compared with studies of OCD and depression(Prod Info LUVOX(R) oral tablets, 2007).
The use of 100 mg/day to 300 mg/day extended-release fluvoxamine maleate has been evaluated in
short-term, placebo-controlled trials of social anxiety disorder (SAD) and OCD. For use in SAD
treatment, 6% of fluvoxamine maleate patients (n=279) reported decreased libido (8% in males and 4%
in females) compared with 4% of placebo patients (n=276) (6% in males and 3% in females). For use in
OCD treatment, 6% of fluvoxamine maleate patients (n=124) reported decreased libido (10% in males
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 27
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
28 of 160
Page 28
of 244
and 4% in females) compared with 2% of placebo patients (n=124) (5% in males and 1% in females)
(Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3.3.14.B.9 Sexual dysfunction
a) Incidence: extended-release (social anxiety disorder), 2% (males), 3% (females); extended-release
(obsessive-compulsive disorder), 4% (males)(Prod Info LUVOX(R) CR extended-release oral capsules,
2008; Prod Info LUVOX(R) oral tablets, 2007)
b) The use of 100 mg/day to 300 mg/day extended-release fluvoxamine maleate has been evaluated in
short-term, placebo-controlled trials of social anxiety disorder (SAD) and OCD. For use in SAD
treatment, 3% of fluvoxamine maleate patients (n=279) reported abnormal sexual function (2% in males
and 3% in females) compared with less than 1% of placebo patients (n=276) (1% in males). For use in
OCD treatment, 4% of male fluvoxamine maleate patients reported abnormal sexual function compared
with 3% of male placebo patients. The incidence was 0% in females (Prod Info LUVOX(R) CR
extended-release oral capsules, 2008).
c) Of 20 healthy volunteers enrolled in a phenotyping study using fluvoxamine, 7 (35%) reported sexual
dysfunction after 4 weeks of fluvoxamine treatment. Fluvoxamine 100 mg daily on Friday and Saturday
followed by 300 mg daily Sunday through Thursday resulted in normal sexual function with adequate
control of depression and obsessive-compulsive symptoms. In humans, it is postulated that serotonin
has an inhibitory effect on sexual function by direct effects on the central, spinal, or peripheral receptors
(Nafziger et al, 1999).
3.3.15 Respiratory Effects
3.3.15.A Fluvoxamine Maleate
Pharyngitis
Rhinitis
Upper respiratory infection
Yawning
3.3.15.A.1 Pharyngitis
a) Incidence: extended-release (obsessive-compulsive disorder), 6% (Prod Info LUVOX(R) CR
extended-release oral capsules, 2008)
b) The use of 100 mg/day to 300 mg/day extended-release fluvoxamine maleate has been evaluated in
short-term, placebo-controlled trials of social anxiety disorder (SAD) and obsessive-compulsive disorder
(OCD). For use in OCD treatment, 6% of fluvoxamine maleate patients (n=124) reported pharyngitis
compared with less than 1% of placebo patients (n=124). For use in SAD treatment, the incidence was
less than or equal to placebo (Prod Info LUVOX(R) CR extended-release oral capsules, 2008). In shortterm, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate (100 mg/day
to 300 mg/day) for the treatment of OCD, pharyngitis was reported at a rate that was two-fold higher
than the rate reported in OCD and depression trials (Prod Info LUVOX(R) oral tablets, 2007).
3.3.15.A.2 Rhinitis
a) Incidence: immediate-release (obsessive-compulsive disorder), at least 5% (Prod Info LUVOX(R)
oral tablets, 2007)
b) In 2 short-term, placebo-controlled studies involving patients with obsessive-compulsive disorder,
rhinitis was reported in 5% or more of patients treated with immediate-release fluvoxamine maleate.
This was at least twice the rate found in placebo-treated patients, and there was a two-fold increase in
the rate of rhinitis in studies of OCD treatment compared with studies of OCD and depression(Prod Info
LUVOX(R) oral tablets, 2007).
3.3.15.A.3 Upper respiratory infection
a) Incidence: immediate-release, 9% (Prod Info LUVOX(R) oral tablets, 2007)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
upper respiratory infection was reported in 9% of fluvoxamine maleate patients (n=892) compared with
5% of placebo patients (n=778) (Prod Info LUVOX(R) oral tablets, 2007).
3.3.15.A.4 Yawning
a) Incidence: immediate-release, 2%; extended-release (social anxiety disorder), 5%; extended-release
(obsessive-compulsive disorder), 2% (Prod Info LUVOX(R) oral tablets, 2007; Prod Info LUVOX(R) CR
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 28
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
29 of 160
Page 29
of 244
extended-release oral capsules, 2008)
b) In short-term, placebo-controlled clinical trials evaluating immediate-release fluvoxamine maleate
(100 mg/day to 300 mg/day) for the treatment of obsessive-compulsive disorder (OCD) or depression,
yawning was reported in 2% of fluvoxamine maleate patients (n=892) compared with 0% of placebo
patients (n=778) (Prod Info LUVOX(R) oral tablets, 2007). The use of 100 mg/day to 300 mg/day
extended-release fluvoxamine maleate has been evaluated in short-term, placebo-controlled trials of
social anxiety disorder (SAD) and OCD. For use in SAD treatment, 5% of fluvoxamine maleate patients
(n=279) reported yawning compared with less than 1% of placebo patients (n=276). For use in OCD
treatment, 2% of fluvoxamine maleate patients (n=124) reported yawning compared with 0% of placebo
patients (n=124) (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3.3.16 Other
Fluvoxamine
Fluvoxamine Maleate
3.3.16.A Fluvoxamine
3.3.16.A.1 Drug withdrawal
See Drug Consult reference: WITHDRAWAL SYNDROME OF SELECTIVE SEROTONIN REUPTAKE
INHIBITORS
3.3.16.B Fluvoxamine Maleate
Accidental injury
Neuroleptic malignant syndrome
Withdrawal sign or symptom
3.3.16.B.1 Accidental injury
a) Incidence: immediate-release, at least 1%; extended-release (obsessive-compulsive disorder), 5%
(Prod Info LUVOX(R) oral tablets, 2007; Prod Info LUVOX(R) CR extended-release oral capsules,
2008)
b) Accidental injury was reported in at least 1% of patients with major depressive disorder or
obsessive-compulsive disorder (OCD) who took immediate-release fluvoxamine maleate during
premarketing clinical trials (Prod Info LUVOX(R) oral tablets, 2007). The use of 100 mg/day to 300
mg/day extended-release fluvoxamine maleate has been evaluated in short-term, placebo-controlled
trials of social anxiety disorder (SAD) and OCD. For use in OCD treatment, 5% of fluvoxamine maleate
patients (n=124) reported accidental injury compared with 3% of placebo patients (n=124). For use in
SAD treatment, the incidence was less than or equal to placebo (Prod Info LUVOX(R) CR extendedrelease oral capsules, 2008).
3.3.16.B.2 Neuroleptic malignant syndrome
a) Incidence: rare (Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Prod Info LUVOX
(R) oral tablets, 2007)
b) While most reports of neuroleptic malignant syndrome (NMS) involved concomitant administration of
fluvoxamine maleate and an antipsychotic drug, a small number of NMS cases have been associated
with the administration of fluvoxamine maleate alone. Symptoms included hyperthermia, muscle rigidity,
autonomic instability, changes in vital signs, and mental status changes (Prod Info LUVOX(R) CR
extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007).
c) Neuroleptic malignant syndrome has been described, with the earliest onset noted at 5 days
(Bronner & Vanneste, 1998), and latest onset at 4 months (Chong, 1995). Duration of symptoms with
treatment is usually a few days (Caley, 1997; Gill et al, 1997).
3.3.16.B.3 Withdrawal sign or symptom
a) Withdrawal symptoms including dysphoric mood, irritability, agitation, dizziness, sensory
disturbances (eg, paresthesias, including electric shock sensations), anxiety, confusion, headache,
lethargy, emotional lability, insomnia, and hypomania have occurred when immediate-release
fluvoxamine maleate was discontinued, primarily if discontinuation is abrupt. These events may be
serious, although they are usually self-limiting. A gradual reduction in dose is recommended and, if
intolerable symptoms develop, a temporary resumption of therapy with the prescribed dose may be
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 29
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
30 of 160
Page 30
of 244
warranted, followed by a more gradual reduction (Prod Info LUVOX(R) CR extended-release oral
capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007).
b) On the fourth day following the abrupt discontinuation of fluvoxamine (200 mg/day), a 12-year-old
boy experienced nausea, poor concentration, lightheadedness, fatigue, headache, gait instability, and
insomnia. Fluvoxamine was restarted at the same dose and the patient's discontinuation symptoms
resolved within 2 days. A second 12-year-old boy developed discontinuation symptoms of headache,
poor concentration, irritability, dizziness, fatigue, and shock-like sensation in the brain 5 days after
stopping fluvoxamine 200 mg/day. Reinstitution of fluvoxamine at the former dose resulted in resolution
of withdrawal symptoms in 3 days (Diler & Avci, 2002).
3.4 Teratogenicity/Effects in Pregnancy/Breastfeeding
A) Teratogenicity/Effects in Pregnancy
1) U.S. Food and Drug Administration's Pregnancy Category: Category C (Prod Info LUVOX(R) oral tablets,
2008) (All Trimesters)
a) Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other)
and there are no controlled studies in women or studies in women and animals are not available. Drugs
should be given only if the potential benefit justifies the potential risk to the fetus.
2) Australian Drug Evaluation Committee's (ADEC) Category: C(Australian Drug Evaluation Committee, 1999)
a) Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing
harmful effects on the human fetus or neonate without causing malformations. These effects may be
reversible. Accompanying texts should be consulted for further details.
See Drug Consult reference: PREGNANCY RISK CATEGORIES
3) Crosses Placenta: Unknown
4) Clinical Management
a) Although human and animal studies of fluvoxamine use during pregnancy did not reveal substantial
teratogenicity (Kulin et al, 1998), nonteratogenic effects (pulmonary hypertension of the newborn (PPHN)
and clinical findings consistent with serotonin syndrome) and increased special or intensive unit care of the
infant were demonstrated following maternal use of fluvoxamine during the third trimester of pregnancy
(Prod Info LUVOX(R) oral tablets, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008;
Malm et al, 2005). A study of prospectively collected data suggests antenatal use of selective serotoninreuptake inhibitor (SSRI) antidepressants is associated with QTc interval prolongation in exposed neonates
(Dubnov-Raz et al, 2008). One study revealed that women who discontinued antidepressant medication
during pregnancy had a greater likelihood of relapse compared with those who continued antidepressant
therapy throughout the pregnancy (Prod Info LUVOX(R) oral tablets, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Therefore, when deciding whether to treat a pregnant woman with
fluvoxamine during the third trimester, evaluate the potential risk to the fetus and the potential benefit to the
mother. Consider tapering the fluvoxamine dose during the third trimester of pregnancy (Prod Info LUVOX
(R) oral tablets, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
5) Literature Reports
a) A study of prospectively collected data suggests antenatal use of selective serotonin-reuptake inhibitor
(SSRI) antidepressants is associated with QTc interval prolongation in exposed neonates. Between January
2000 and December 2005, researchers compared 52 neonates exposed to SSRI antidepressants
(paroxetine (n=25), citalopram (n=13), fluoxetine (n=12), fluvoxamine (n=1), and venlafaxine (n=1)) in the
immediate antenatal period to 52 matched neonates with no exposure. Prolonged QTc is defined as an
interval of greater than 460 milliseconds (msec) (the widely used upper limit cited by authorities in both
pediatric cardiology and neonatology). A pediatric cardiologist blinded to drug exposure, interpreted all
electrocardiograms (ECGs) using standard statistical analyses. ECG recordings revealed markedly
prolonged mean QTc intervals in exposed neonates compared to unexposed neonates (mean; 409 +/- 42
msec versus 392 +/- 29 msec, p=0.02). The mean uncorrected QT interval was 7.5% longer among exposed
neonates (mean; 280 +/- 31 msec versus 261 +/- 25 msec, p less than 0.001). Ten percent (n=5) of exposed
neonates had a notable increase in QTc interval prolongation (greater than 460 msec) compared to none of
the unexposed neonates. The longest QTc interval observed was 543 msec (Dubnov-Raz et al, 2008).
b) Neonates exposed to fluvoxamine and other SSRIs late in the third trimester have developed
complications, including respiratory distress, seizures, vomiting, tremor, and irritability that were consistent
with either SSRI toxicity or a possible drug discontinuation syndrome. In some cases, clinical findings were
consistent with serotonin syndrome (Prod Info LUVOX(R) oral tablets, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008).
c) In a case control study of women who delivered infants with pulmonary hypertension of the newborn
(PPHN; n=377) and women who delivered healthy infants (n=836), the risk for developing PPHN was
approximately six-fold higher in infants exposed to SSRIs after week 20 of gestation compared with infants
not exposed to SSRIs during gestation. This study demonstrates a potential increased risk of PPHN,
associated with considerable neonatal morbidity and mortality, in infants exposed to SSRIs later in the
pregnancy. In the general population, PPHN occurs in 1 to 2 per 1000 live births (Prod Info LUVOX(R) oral
tablets, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
d) In a prospective longitudinal study of 201 women with a history of major depression and no signs of
depression at the beginning of pregnancy, there was a greater likelihood of relapse of major depression in
those who discontinued antidepressant drugs during pregnancy compared with those who continued
antidepressant drugs throughout the pregnancy (Prod Info LUVOX(R) oral tablets, 2008; Prod Info LUVOX
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 30
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
31 of 160
Page 31
of 244
(R) CR extended-release oral capsules, 2008).
e) A population-based study of 1782 pregnant women exposed to SSRIs found no increased risk of adverse
perinatal outcome except for treatment in the neonatal intensive or special care unit, particularly with third
trimester exposure. Using 1996-2001 data derived from a government project involving 4 birth or medication
registries in Finland, women who had at least one purchase (a 3-month supply) of an SSRI during the period
of one month before pregnancy and the day pregnancy ended were compared with 1782 controls with no
reimbursed drug purchases during the same peripartum period. The mean age of both cohorts was 30 years
(+/- 7). There were more than twice as many smokers and six times as many pregnancies induced by
artificial reproductive techniques in the SSRI group compared to controls (p less than 0.001), and mean
length of gestation and birth weight were lower (p less than 0.001) in the SSRI group. Malformations,
however, were not more common in the SSRI group (p = 0.4). Purchases of SSRIs (citalopram, fluoxetine,
paroxetine, sertraline and fluvoxamine) were more common in the first trimester than later in pregnancy, with
65 women purchasing fluvoxamine during the first trimester, 23 during the second trimester, 27 during the
third, and 10 throughout pregnancy. When compared with first trimester exposure, treatment in a special or
intensive care unit was more common for the infants exposed during the third trimester (11.2% and 15.7%,
respectively; p = 0.009). Even after adjusting for confounding variables, this difference remained statistically
significant (OR 1.6; 95% CI 1.1-2.2) (Malm et al, 2005).
f) In a cohort study (n=267), the pregnancy outcome did not differ between women treated with sertraline
(n=147), paroxetine (n=97), or fluvoxamine (n=26) versus controls. Rates of major malformations, stillbirth,
and spontaneous and elective abortions were similar between the 2 groups as were the mean birth rate and
gestational age. Nine major malformations were detected in infants exposed to a selective serotonin
reuptake inhibitor (SSRI) and in control infants. Of the 49 women who were treated throughout pregnancy
with an SSRI, there were also no differences in outcome compared to women treated only during the first
trimester. The majority of women took sertraline 50 mg/day, paroxetine 30 mg/day, and fluvoxamine 50
mg/day (Kulin et al, 1998).
g) Treatment with fluvoxamine 200 mg/day and quetiapine 400 mg/day in a 33-year-old woman during her
second pregnancy resulted in an uneventful pregnancy and the birth of a healthy female infant. The patient
was being treated with fluvoxamine and quetiapine when she was diagnosed with a severe postpartum
psychotic depression after the birth of her first child; multiple attempts at reducing her medication led to
relapse. After being informed of the risks-benefits of fluvoxamine/quetiapine exposure during pregnancy, the
patient decided to go forward with a second pregnancy while maintaining her drug regimen of fluvoxamine
and quetiapine with the addition of folate 5 mg/day throughout the pregnancy. The patient gained 9 kg with
no symptoms of psychiatric instability. Routine biochemical tests were within the normal range and 5
echographic reports found no fetal abnormalities. The presence of an intrauterine myoma led to an elective
caesarean-section. A healthy female infant weighing 2600 g and measuring 49 cm in length was delivered,
with Apgar scores of 9 and 10 at 1 minute and 5 minutes, respectively (Gentile, 2006).
B) Breastfeeding
1) American Academy of Pediatrics Rating: Drugs for which the effect on nursing infants is unknown but may be
of concern. (Anon, 2001)
2) Thomson Lactation Rating: Infant risk cannot be ruled out.
a) Available evidence and/or expert consensus is inconclusive or is inadequate for determining infant risk
when used during breastfeeding. Weigh the potential benefits of drug treatment against potential risks
before prescribing this drug during breastfeeding.
3) Clinical Management
a) The American Academy of Pediatrics considers antidepressants to be drugs worthy of concern in the
nursing infant, particularly during long-term use (Anon, 2001). The long-term effects of exposure to SSRIs
via breast milk on the cognitive development of the infant have not been determined. Although fluvoxamine
appeared in the breast milk of two nursing mothers, the drug was not observed in the plasma of either infant
and both developed normally with no adverse effects (Kristensen et al, 2002). Similarly, in a case report of a
nursing woman being treated with fluvoxamine/quetiapine, the nursing infant received breast milk
supplemented with formula for 3 months and showed no developmental abnormalities (Gentile, 2006).
Because fluvoxamine is secreted in human breast milk and there is potential for serious adverse effects in
the nursing infant, a decision should be made whether to discontinue the drug or discontinue nursing, taking
into consideration the potential risk to the fetus as well as the potential benefit to the mother (Prod Info
LUVOX(R) oral tablets, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008; Kristensen et
al, 2002).
4) Literature Reports
a) Treatment with fluvoxamine 200 mg/day and quetiapine 400 mg/day in a 33-year-old woman during her
second pregnancy resulted in an uneventful pregnancy and the birth of a healthy female infant weighing
2600 g and measuring 49 cm in length with Apgar scores of 9 and 10 at 1 minute and 5 minutes,
respectively. The patient chose to breast-feed; however, formula was required to supplement her breast milk
due to insufficient milk production. In the 3 months that the infant received breast milk supplemented with
formula, no adverse effects were detected and the infant continues to develop normally (Gentile, 2006).
b) In a study of 2 mother-infant pairs, there were no adverse effects from fluvoxamine found in either
nursing infant. The infants were 26 months and 0.75 months of age at the time of the study, which involved
collecting venous blood samples and breast milk over a 24 hour dosing interval. Assuming a milk intake for
both infants of 0.15 L/kg/day, the infant dose calculated as a percentage of the weight-adjusted maternal
dose were 1.38% (26 month old infant) and 0.8% (0.75 month old infant). The milk to plasma ratios were
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 31
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
32 of 160
Page 32
of 244
1.34 and 1.21, respectively. Fluvoxamine was not detected in the plasma of either infant. The 26-month-old
infant had a Denver developmental assessment with a quotient of 115, indicating that the infant achieved the
anticipated milestones. The 0.75-month-old infant was too young to have a meaningful Denver assessment,
so a detailed pediatric examination was performed and found no abnormalities. Both mothers reported that
the health and progress of their infants was satisfactory (Kristensen et al, 2002).
5) Drug Levels in Breastmilk
a) Fluvoxamine Maleate
1) Parent Drug
a) Percent Adult Dose in Breastmilk
1) In a study of 2 mother-infant pairs, the infant dose calculated as a percentage of the weight
adjusted maternal dose were 0.8% (0.75 month old infant) and 1.38% (26 month old infant).
These values assume an average milk intake of 0.15 liters/kilogram (L/kg) per day (Kristensen
et al, 2002).
b) Milk to Maternal Plasma Ratio
1) In a study of 2 mother-infant pairs, the milk to maternal plasma ratio were 1.21 (0.75 month
old infant) and 1.34 (26 month old infant) (Kristensen et al, 2002).
c) Time to Peak Concentration in Milk
1) In a study of 2 mother-infant pairs, the time after dose at which maximum fluvoxamine
concentrations were achieved in breast milk were 2.1 hours (0.75 month old infant) and 4.2
hours (26 month old infant) (Kristensen et al, 2002).
3.5 Drug Interactions
Drug-Drug Combinations
Drug-Food Combinations
Drug-Tobacco Combinations
3.5.1 Drug-Drug Combinations
Abciximab
Aceclofenac
Acemetacin
Acenocoumarol
Alclofenac
Almotriptan
Alosetron
Alprazolam
Amitriptyline
Anagrelide
Ancrod
Anisindione
Antithrombin III Human
Ardeparin
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 32
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
33 of 160
Page 33
of 244
Aspirin
Astemizole
Bendamustine
Benoxaprofen
Bivalirudin
Bromfenac
Bufexamac
Bupropion
Cannabis
Carbamazepine
Carprofen
Celecoxib
Certoparin
Cilostazol
Cisapride
Clomipramine
Clonixin
Clopidogrel
Clopidogrel
Clorgyline
Clozapine
Cyclosporine
Dalteparin
Danaparoid
Defibrotide
Dehydroepiandrosterone
Dermatan Sulfate
Desipramine
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 33
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
34 of 160
Page 34
of 244
Desirudin
Desvenlafaxine
Dexfenfluramine
Dexketoprofen
Diazepam
Diclofenac
Dicumarol
Diflunisal
Dihydroergotamine
Diltiazem
Dipyridamole
Dipyrone
Droperidol
Droxicam
Duloxetine
Eletriptan
Eltrombopag
Enoxaparin
Epoprostenol
Eptifibatide
Ergoloid Mesylates
Ergonovine
Ergotamine
Estazolam
Etodolac
Etofenamate
Etoricoxib
Felbinac
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 34
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
35 of 160
Page 35
of 244
Fenbufen
Fenfluramine
Fenoprofen
Fentiazac
Floctafenine
Flufenamic Acid
Flurbiprofen
Fondaparinux
Fosphenytoin
Frovatriptan
Furazolidone
Galantamine
Ginkgo
Glimepiride
Guarana
Haloperidol
Heparin
Hydroxytryptophan
Ibuprofen
Iloprost
Imipramine
Indomethacin
Indoprofen
Iproniazid
Isocarboxazid
Isoxicam
Ketoprofen
Ketorolac
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 35
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
36 of 160
Page 36
of 244
Lamifiban
Levomethadyl
Lexipafant
Linezolid
Lithium
Lornoxicam
Maprotiline
Mate
Meclofenamate
Mefenamic Acid
Melatonin
Meloxicam
Methadone
Methylergonovine
Methylphenidate
Metoprolol
Mexiletine
Midazolam
Milnacipran
Mirtazapine
Moclobemide
Morniflumate
Nabumetone
Nadroparin
Naproxen
Naratriptan
Nialamide
Niflumic Acid
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 36
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
37 of 160
Page 37
of 244
Nimesulide
Olanzapine
Oxaprozin
Oxycodone
Parecoxib
Pargyline
Parnaparin
Pentosan Polysulfate Sodium
Phenelzine
Phenindione
Phenprocoumon
Phenylbutazone
Phenytoin
Pirazolac
Piroxicam
Pirprofen
Procarbazine
Propranolol
Propyphenazone
Proquazone
Ramelteon
Rasagiline
Reviparin
Rizatriptan
Rofecoxib
Ropivacaine
Selegiline
Sibrafiban
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 37
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
38 of 160
Page 38
of 244
Sibutramine
St John's Wort
Sulfinpyrazone
Sulindac
Sulodexide
Sumatriptan
Suprofen
Tacrine
Tapentadol
Tenidap
Tenoxicam
Terfenadine
Theophylline
Thioridazine
Tiaprofenic Acid
Ticlopidine
Tinzaparin
Tirofiban
Tizanidine
Tolmetin
Toloxatone
Tramadol
Tranylcypromine
Triazolam
Tryptophan
Valdecoxib
Warfarin
Xemilofiban
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 38
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
39 of 160
Page 39
of 244
Zolmitriptan
Zomepirac
3.5.1.A Abciximab
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and antiplatelet agents has been associated
with an increased risk of bleeding. Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008;
Prod Info PROZAC(R) oral capsules, delayed-release capsules, solution, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an antiplatelet agent are given concurrently, monitor patient for
signs of increased bleeding (Prod Info PAXIL(R) oral tablets, suspension, 2008; Prod Info PROZAC(R) oral
capsules, delayed-release capsules, solution, 2008)
7) Probable Mechanism: unknown
3.5.1.B Aceclofenac
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.C Acemetacin
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 39
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
40 of 160
Page 40
of 244
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.D Acenocoumarol
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.E Alclofenac
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 40
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
41 of 160
Page 41
of 244
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.F Almotriptan
1) Interaction Effect: an increased risk of serotonin syndrome
2) Summary: Concomitant use of almotriptan and selective serotonin reuptake inhibitors (SSRI's) has been
reported to cause weakness, hyperreflexia, and incoordination (Prod Info Axert(TM), 2001). Concurrent use
of a triptan and an SSRI may result in serotonin syndrome which may be life-threatening. Symptoms of
serotonin syndrome may include restlessness, hallucinations, loss of coordination, fast heart beat, rapid
changes in blood pressure, increased body temperature, overreactive reflexes, nausea, vomiting, and
diarrhea. Clinicians should be aware that triptans may be commonly used intermittently and that either the
triptan or the SSRI may be prescribed by a different physician. Discuss the risks of serotonin syndrome with
patients who are prescribed this combination and monitor them closely for symptoms of serotonin syndrome
(US Food and Drug Administration, 2006).
3) Severity: major
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Coadministration of a triptan, such as almotriptan, and an SSRI may result in a lifethreatening condition called serotonin syndrome. Be aware that triptans may be commonly used
intermittently and that either the triptan or the SSRI may be prescribed by a different physician. If these
agents are used together, discuss the risks of serotonin syndrome with the patient and monitor closely for
symptoms of serotonin syndrome (restlessness, hyperthermia, hyperreflexia, incoordination).
7) Probable Mechanism: additive pharmacologic effects resulting in excessive serotonergic stimulation
8) Literature Reports
a) Concomitant administration of fluoxetine and almotriptan is well tolerated and fluoxetine has only a
modest effect on almotriptan maximum plasma concentration (Cmax). Other almotriptan
pharmacokinetics are not significantly affected. A randomized, open-label, two-way crossover study
involving 14 healthy volunteers has been conducted. Subjects received each of the following treatments
with a minimum 3-week washout between periods: (1) three 20 mg fluoxetine capsules on day 1 to 8
and one dose almotriptan 12.5 mg on day 8, (2) one dose of almotriptan 12.5 mg on day 8 with no
treatment on days 1 through 7. Peak almotriptan concentrations were 18% higher following concomitant
administration of fluoxetine than after almotriptan administration alone. This difference was statistically
significant (p equal 0.023). Mean almotriptan area under the concentration-time curve (AUC) and oral
clearance were borderline statistically different between treatment groups. Mean half-life was not
statistically different between the treatment groups. During fluoxetine coadministration, Tmax was
shorter, suggesting that the absorption rate of almotriptan may have been increased by fluoxetine. The
author concludes that based on the results of this study and the lack of effect of fluoxetine on
almotriptan pharmacokinetics, almotriptan and fluoxetine can be safely used concomitantly in migraine
management (Fleishaker et al, 2001).
3.5.1.G Alosetron
1) Interaction Effect: increased alosetron exposure and increased side effects
2) Summary: Fluvoxamine is a potent inhibitor of the CYP1A2-mediated metabolism of alosetron. In a
pharmacokinetic study of 40 healthy female subjects, fluvoxamine increased mean alosetron AUC by 6-fold
and prolonged alosetron half-life by 3-fold. Concomitant use of fluvoxamine and alosetron is contraindicated
due to the increased risk of serious bowel side effects, including ischemic colitis (Prod Info LOTRONEX(R),
2005).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: established
6) Clinical Management: Concomitant use of alosetron and fluvoxamine is contraindicated. Monitor patient
for bowel side effects including constipation, abdominal or gastrointestinal pain or discomfort, nausea,
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 41
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
42 of 160
Page 42
of 244
abdominal distention, reflux and hemorrhoids. Watch for signs and symptoms of ischemic colitis including
rectal bleeding, bloody diarrhea or new or worsening abdominal pain.
7) Probable Mechanism: inhibition by fluvoxamine of CYP1A2-mediated alosetron metabolism
8) Literature Reports
a) Fluvoxamine inhibits the CYP1A2-mediated metabolism of alosetron. In a pharmacokinetic study
involving 40 healthy female subjects, participants received an escalating dose of fluvoxamine 50 to 200
mg daily for 16 days. On the final day, participants also received a single 1 mg dose of alosetron. The
area under the concentration-time curve (AUC) and half-life of alosetron increased 6-fold and 3-fold,
respectively (Prod Info LOTRONEX(R), 2005).
3.5.1.H Alprazolam
1) Interaction Effect: elevated plasma alprazolam levels and an increased risk of side effects (CNS
depression)
2) Summary: Fluvoxamine coadministration (100 mg daily) with alprazolam 1 mg four times daily resulted in
a 2-fold increase in alprazolam steady-state plasma concentrations, area under the concentration-time curve
(AUC), maximum concentration (Cmax), and half-life. Elevated plasma levels of alprazolam were associated
with impaired psychomotor performance and memory. This effect may be even more pronounced with
higher fluvoxamine doses (300 mg daily) (Prod Info Luvox(R), 1997x).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: If alprazolam is given to a patient already on fluvoxamine, the initial alprazolam
dose should be reduced by 50% due to the possibility of significant alprazolam accumulation. Monitor for
signs of alprazolam intoxication (eg, sedation, dizziness, ataxia, weakness, decreased cognition or motor
performance) or consider switching to a benzodiazepine eliminated by glucuronidation (eg, lorazepam,
oxazepam, temazepam).
7) Probable Mechanism: inhibition by fluvoxamine of cytochrome P4503A4-mediated alprazolam
metabolism
3.5.1.I Amitriptyline
1) Interaction Effect: amitriptyline toxicity (dry mouth, urinary retention, sedation)
2) Summary: Coadministration of fluvoxamine and amitriptyline was found to significantly increase plasma
levels of amitriptyline (Bertschy et al, 1991a). A bidirectional effect was suggested in which fluvoxamine
increased amitriptyline concentrations (by interfering with N-demethylation) and amitriptyline increased
fluvoxamine levels (Hartter et al, 1993a).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Monitor patients for signs of amitriptyline and fluvoxamine toxicity; lower doses of
one or both agents may be required with concomitant therapy.
7) Probable Mechanism: decreased amitriptyline metabolism
8) Literature Reports
a) Fluvoxamine has been shown to significantly increase plasma levels of amitriptyline and
clomipramine and to mildly increase levels of their metabolites nortriptyline and desmethylclomipramine,
respectively. This may be due to competitive inhibition of oxidative metabolism in the liver (Bertschy et
al, 1991).
b) Metabolism of tricyclic antidepressants coadministered with fluvoxamine was studied in eight
depressed patients (one patient received amitriptyline) (Hartter et al, 1993). Fluvoxamine was found to
interfere with N-demethylation of amitriptyline. The combination of fluvoxamine and amitriptyline led to
increased plasma levels of amitriptyline and decreased concentrations of amitriptyline's N-demethylated
metabolite, nortriptyline. In addition, plasma levels of fluvoxamine were increased.
3.5.1.J Anagrelide
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and antiplatelet agents has been associated
with an increased risk of bleeding. Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008;
Prod Info PROZAC(R) oral capsules, delayed-release capsules, solution, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an antiplatelet agent are given concurrently, monitor patient for
signs of increased bleeding (Prod Info PAXIL(R) oral tablets, suspension, 2008; Prod Info PROZAC(R) oral
capsules, delayed-release capsules, solution, 2008)
7) Probable Mechanism: unknown
3.5.1.K Ancrod
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 42
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
43 of 160
Page 43
of 244
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.L Anisindione
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 43
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
44 of 160
Page 44
of 244
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.M Antithrombin III Human
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 44
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
45 of 160
Page 45
of 244
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.N Ardeparin
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 45
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
46 of 160
Page 46
of 244
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.O Aspirin
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and antiplatelet agents has been associated
with an increased risk of bleeding. Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008;
Prod Info PROZAC(R) oral capsules, delayed-release capsules, solution, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an antiplatelet agent are given concurrently, monitor patient for
signs of increased bleeding (Prod Info PAXIL(R) oral tablets, suspension, 2008; Prod Info PROZAC(R) oral
capsules, delayed-release capsules, solution, 2008)
7) Probable Mechanism: unknown
3.5.1.P Astemizole
1) Interaction Effect: cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Fluvoxamine should not be used in combination with astemizole. Fluvoxamine appears to be a
potent inhibitor of the cytochrome P450IIIA4 isozyme, the enzyme primarily responsible for metabolizing
astemizole. Inhibition of this enzyme may result in elevated astemizole concentrations; increased plasma
concentrations of astemizole are associated with QT prolongation and torsades de pointes, which can be
fatal (Prod Info Luvox(R), 1997j; Prod Info Hismanal(R), 1998).
3) Severity: contraindicated
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Concurrent use of astemizole and fluvoxamine is contraindicated.
7) Probable Mechanism: inhibition by fluvoxamine of astemizole metabolism
3.5.1.Q Bendamustine
1) Interaction Effect: increased bendamustine levels and decreased levels of active minor metabolites of
bendamustine
2) Summary: Alternative treatments should be considered when concomitant use of bendamustine with a
CYP1A2 inhibitor is necessary. Based on in vitro data, bendamustine is primarily metabolized via CYP1A2
into 2 active minor metabolites (M3 and M4). However, the cytotoxic efficacy is primarily due to the parent
compound as the active metabolites have very low plasma concentrations. Concomitant administration of a
strong CYP1A2 inhibitor, such as fluvoxamine, may result in increased bendamustine concentrations and
decreased concentrations of the metabolites (Prod Info TREANDA(R) IV injection, 2008). If used
concomitantly, patients should be closely monitored for increased incidence of bendamustine adverse
events (myelosuppression, infection, skin reactions) and doses should be adjusted appropriately.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Consider alternative treatment when concomitant use of bendamustine with a
strong CYP1A2 inhibitor, such as fluvoxamine, is required. However, use caution if bendamustine and
fluvoxamine are coadministered (Prod Info TREANDA(R) IV injection, 2008). Monitor the patient for
increased bendamustine adverse events (myelosuppression, infection, skin reactions) and adjust doses as
necessary.
7) Probable Mechanism: inhibition of the CYP1A2-mediated bendamustine metabolism
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 46
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
47 of 160
Page 47
of 244
3.5.1.R Benoxaprofen
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.S Bivalirudin
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 47
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
48 of 160
Page 48
of 244
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.T Bromfenac
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.U Bufexamac
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.V Bupropion
1) Interaction Effect: increased plasma levels of bupropion
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 48
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
49 of 160
Page 49
of 244
2) Summary: In vitro studies suggest that fluvoxamine inhibits the hydroxylation of bupropion which may
result in increased bupropion concentrations when the two agents are used concurrently. Use caution when
bupropion and fluvoxamine are coadministered and monitor patients for excessive bupropion adverse
effects (agitation, anxiety, insomnia, hallucinations) (Prod Info WELLBUTRIN(R) oral tablets, 2008).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Concomitant use of bupropion and fluvoxamine may cause elevated bupropion
concentrations. Monitor patients for excessive bupropion adverse effects (agitation, anxiety, insomnia,
hallucinations) when fluvoxamine is being administered concurrently (Prod Info WELLBUTRIN(R) oral
tablets, 2008).
7) Probable Mechanism: inhibition of the hydroxylation of bupropion by fluvoxamine
8) Literature Reports
a) In vitro studies suggest that fluvoxamine inhibits the hydroxylation of bupropion. No clinical studies
have been conducted to verify this finding (Prod Info WELLBUTRIN(R) oral tablets, 2008).
3.5.1.W Cannabis
1) Interaction Effect: manic symptoms
2) Summary: One case of mania following use of marijuana with fluoxetine therapy has been reported (Stoll
et al, 1991a). Although an interaction is proposed, the authors also state the manic symptoms could have
resulted from the fluoxetine or marijuana alone. Caution is advised for patients using marijuana and taking
fluoxetine or other serotonin reuptake inhibitors.
3) Severity: moderate
4) Onset: rapid
5) Substantiation: theoretical
6) Clinical Management: Caution patients taking selective serotonin reuptake inhibitors to avoid concomitant
use of marijuana.
7) Probable Mechanism: additive serotonergic stimulation
8) Literature Reports
a) A 21-year-old female presented with mania, agitation, and grandiose delusions following use of
marijuana with fluoxetine therapy. She had been taking fluoxetine 20 mg daily for 4 weeks and reported
smoking 2 "joints" during a 36-hour period. Over the next 24 hours, she developed increased energy,
hypersexuality, pressured speech, and grandiose delusions. Lorazepam and perphenazine were given
for agitation and excitement which gradually resolved over 4 days. She remained hospitalized for 36
days. Fluoxetine 20 mg every other day was reintroduced one week prior to discharge. One week after
discharge, she discontinued fluoxetine due to insomnia and feeling "hyper". These symptoms resolved
rapidly upon discontinuation of fluoxetine. Due to the rapid switch to mania after smoking marijuana with
fluoxetine, the manic symptoms were associated with the concomitant use of fluoxetine and marijuana,
though mania could have developed from either fluoxetine or marijuana alone (Stoll et al, 1991).
3.5.1.X Carbamazepine
1) Interaction Effect: carbamazepine toxicity (ataxia, nystagmus, diplopia, headache, vomiting, apnea,
seizures, coma)
2) Summary: Several cases have been reported in which fluvoxamine appeared to cause increased
carbamazepine levels and symptoms of carbamazepine toxicity (Martinelli et al, 1993; Fritze et al, 1991a).
However, one study of eight epileptic patients found no such increase in carbamazepine levels with three
weeks of concurrent use (Spina et al, 1993e).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Due to the potential to increase carbamazepine levels, patients should be
monitored for evidence of carbamazepine toxicity when fluvoxamine is added to therapy. Carbamazepine
levels should be considered when adding or discontinuing fluvoxamine, with dosage adjustments made as
indicated.
7) Probable Mechanism: decreased carbamazepine metabolism
8) Literature Reports
a) The addition of fluvoxamine to a constant dosage of carbamazepine in three patients caused an
increase in carbamazepine levels resulting in symptoms of toxicity (Fritze et al, 1991). The authors
concluded that this resulted from inhibition of carbamazepine metabolism. However, (Spina et al,
1993d) found no increase in carbamazepine levels in eight epileptic patients who were given
fluvoxamine 100 mg daily or fluoxetine 20 mg daily with carbamazepine for three weeks.
3.5.1.Y Carprofen
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 49
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
50 of 160
Page 50
of 244
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.Z Celecoxib
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.AA Certoparin
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 50
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
51 of 160
Page 51
of 244
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.AB Cilostazol
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and antiplatelet agents has been associated
with an increased risk of bleeding. Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008;
Prod Info PROZAC(R) oral capsules, delayed-release capsules, solution, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an antiplatelet agent are given concurrently, monitor patient for
signs of increased bleeding (Prod Info PAXIL(R) oral tablets, suspension, 2008; Prod Info PROZAC(R) oral
capsules, delayed-release capsules, solution, 2008)
7) Probable Mechanism: unknown
3.5.1.AC Cisapride
1) Interaction Effect: cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Fluvoxamine should not be used in combination with cisapride. Although there is no direct
experience with this combination, fluvoxamine appears to be a potent inhibitor of the cytochrome P450 3A4
isozyme, the enzyme primarily responsible for the metabolism of cisapride. Inhibition of this enzyme may
result in elevated cisapride concentrations; increased plasma concentrations of cisapride are associated
with QT prolongation and torsades de pointes, which can be fatal (Prod Info Luvox(R), 1997u).
3) Severity: contraindicated
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Concurrent use of fluvoxamine and cisapride is contraindicated.
7) Probable Mechanism: inhibition of cytochrome P450 3A4-mediated cisapride metabolism
3.5.1.AD Clomipramine
1) Interaction Effect: clomipramine toxicity (dry mouth, urinary retention, sedation)
2) Summary: Coadministration of fluvoxamine and clomipramine was found to significantly increase plasma
levels of clomipramine (Bertschy et al, 1991c). A bidirectional effect was suggested in which fluvoxamine
increased clomipramine concentrations (by interfering with N-demethylation) and clomipramine increased
fluvoxamine levels (Hartter et al, 1993c).
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 51
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
52 of 160
Page 52
of 244
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Monitor patients for signs of clomipramine and fluvoxamine toxicity; lower doses of
one or both agents may be required with concomitant therapy.
7) Probable Mechanism: decreased clomipramine metabolism
8) Literature Reports
a) Fluvoxamine has been shown to significantly increase plasma levels of amitriptyline and
clomipramine and to mildly increase levels of their metabolites nortriptyline and desmethylclomipramine,
respectively. This may be due to competitive inhibition of oxidative metabolism in the liver (Bertschy et
al, 1991b).
b) Metabolism of tricyclic antidepressants coadministered with fluvoxamine was studied in eight
depressed patients (four patients received clomipramine). Fluvoxamine was found to interfere with Ndemethylation and 8-hydroxylation of clomipramine. The combination of fluvoxamine and clomipramine
led to increased plasma levels of clomipramine and decreased concentrations of clomipramine's Ndemethylated metabolite, desmethylclomipramine. In addition, plasma levels of fluvoxamine were
increased (Hartter et al, 1993b).
3.5.1.AE Clonixin
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.AF Clopidogrel
1) Interaction Effect: reduction in clinical efficacy of clopidogrel
2) Summary: Clopidogrel is metabolized to its active metabolite by CYP2C19. Concomitant use of
CYP2C19 inhibitors, such as fluvoxamine, would be expected to result in reduced levels of the active
metabolite, and therefore a reduction the clinical efficacy of clopidogrel. Concomitant use of CYP2C19
inhibitors with clopidogrel is discouraged (Prod Info PLAVIX(R) oral tablet, 2009).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Concomitant use of clopidogrel and fluvoxamine is discouraged (Prod Info PLAVIX
(R) oral tablet, 2009).
7) Probable Mechanism: inhibition of CYP2C19- mediated clopidogrel metabolism by fluvoxamine
3.5.1.AG Clopidogrel
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and antiplatelet agents has been associated
with an increased risk of bleeding. Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008;
Prod Info PROZAC(R) oral capsules, delayed-release capsules, solution, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an antiplatelet agent are given concurrently, monitor patient for
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 52
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
53 of 160
Page 53
of 244
signs of increased bleeding (Prod Info PAXIL(R) oral tablets, suspension, 2008; Prod Info PROZAC(R) oral
capsules, delayed-release capsules, solution, 2008)
7) Probable Mechanism: unknown
3.5.1.AH Clorgyline
1) Interaction Effect: CNS toxicity or serotonin syndrome (hypertension, hyperthermia, myoclonus, mental
status changes)
2) Summary: Concurrent administration or overlapping therapy with fluvoxamine and a monoamine oxidase
(MAO) inhibitor may result in CNS toxicity or serotonin syndrome, a hyperserotonergic state characterized
by symptoms such as restlessness, myoclonus, changes in mental status, hyperreflexia, diaphoresis,
shivering, and tremor. Serious, even fatal, reactions have been reported with concomitant use of serotonin
specific reuptake inhibitors and MAO inhibitors (Prod Info Luvox(R), 1997k; Lappin & Auchincloss, 1994e;
Graber et al, 1994e; Suchowersky & de Vries, 1990e). Concomitant use is not recommended.
3) Severity: major
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Concurrent use of fluvoxamine and a MAO inhibitor should be avoided. Wait at
least two weeks after discontinuing an MAO inhibitor before initiating therapy with fluvoxamine. Wait at least
two weeks after discontinuing fluvoxamine before initiating therapy with a MAO inhibitor.
7) Probable Mechanism: serotonin reuptake inhibition
8) Literature Reports
a) Concomitant use of serotonin specific reuptake inhibitors and monoamine oxidase inhibitors can
produce a toxic reaction known as serotonin syndrome (Sternbach, 1991d). Serotonin syndrome is a
condition of serotonergic hyperstimulation and manifests as restlessness, myoclonus, changes in
mental status, hyperreflexia, diaphoresis, shivering, and tremor. If the syndrome is not recognized and
correctly treated, death can result.
b) A 26-year old woman who had been taking isocarboxazid for eight weeks stopped taking the drug
for 11 days before beginning therapy with sertraline. After a single 100 mg sertraline dose, the patient
became restless and developed leg twitches. The patients was later admitted to the emergency room
with diaphoresis, tachycardia, hyperreflexia, and various neuromuscular disturbances. After treatment
with diazepam and propranolol the patient did not improve. The patient was then given two 4 mg doses
of cyproheptadine an hour apart, with notable improvement in symptoms after the second dose (Lappin
& Auchincloss, 1994d).
c) A drug interaction occurred in a 61-year old woman whose regimen of sertraline 100 mg twice daily
was added to a regimen of lithium, phenelzine, thioridazine, and doxepin. Three hours after taking the
first sertraline dose, the patient was found in a semicomatose state, with elevated body temperature,
increased pulse, increased respiration rate, and a blood pressure of 140/110 mm Hg. After
transportation to the hospital, the patient was misdiagnosed as having neuroleptic malignant syndrome
(NMS) which was later changed to serotonin syndrome due to a reaction between sertraline and
phenelzine. The authors suggest that monoamine oxidase inhibitor (MAOI) therapy should be
discontinued for at least two weeks before initiation of therapy with a selective serotonin reuptake
inhibitor (SSRI) and that before starting a MAOI, SSRI therapy should be discontinued for at least 5
half-lives of the parent drug and any active metabolites (Graber et al, 1994d).
d) Two cases reports suggested a possible interaction between fluoxetine and selegiline (Suchowersky
& de Vries, 1990d). One case involved a first episode of mania being observed approximately one
month after adding selegiline to fluoxetine therapy. The patient improved two months after both drugs
were discontinued, and no further details were provided. The second case involved diaphoresis,
vasoconstriction, and cyanosis of the hands which occurred in close temporal relationship to adding
fluoxetine and selegiline. Both drugs were discontinued, with relatively quick resolution of symptoms.
Rechallenge with fluoxetine alone occurred without incident.
3.5.1.AI Clozapine
1) Interaction Effect: increased serum clozapine concentrations
2) Summary: Coadministration of clozapine with fluvoxamine has been reported to result in increased
clozapine levels and worsening of psychotic symptoms (Prod Info Clozaril(R), 2002; Chong et al, 1997a;
Jerling et al, 1994a). Extrapyramidal symptoms have also been reported with this drug combination (Kuo et
al, 1998a). Fluvoxamine, a potent inhibitor of CYP1A2, may decrease metabolism of clozapine, resulting in
increased serum concentrations (Chong et al, 1997a; Wetzel et al, 1998a).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Clinicians should be aware of a potential interaction between clozapine and
fluvoxamine. If these drugs are given concurrently, monitor patients for increased serum clozapine
concentrations, worsening of psychosis, and the development of extrapyramidal symptoms. Downward
dosage adjustments of clozapine may be necessary.
7) Probable Mechanism: inhibition of cytochrome P450 1A2-mediated clozapine metabolism
8) Literature Reports
a) Therapeutic drug monitoring data showed higher clozapine concentration/dose ratios in three of four
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 53
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
54 of 160
Page 54
of 244
patients when concurrent fluvoxamine was used compared with clozapine alone. In two of these
patients, clozapine concentrations were 5 to 10 times higher when fluvoxamine was coadministered.
One patient experienced adverse effects, including sedation and urinary incontinence. Inhibition of the
CYP1A2 enzyme by fluvoxamine was thought to be the mechanism in this drug interaction (Jerling et al,
1994).
b) One study presented two case reports in which addition of a selective serotonin reuptake inhibitor
(SSRI) to clozapine therapy resulted in exacerbation of psychotic symptoms. The first patient, a 26-year
old woman with schizophrenia, had been taking clozapine 175 mg per day. Other medications included
propranolol for tachycardia and trihexyphenidyl for hypersalivation. After marked improvement in
psychotic symptoms but continued compulsive behavior, sertraline 50 mg per day was added. Within
four weeks, the patient's obsessive-compulsive symptoms and psychotic symptoms worsened. Plasma
clozapine concentrations increased from 325 ng/mL before sertraline therapy to 695 ng/mL after
sertraline therapy. Patient 2, a 24-year old woman with schizophrenia, was placed on a regimen of
clozapine 500 mg per day which was later increased to 600 mg per day. After fluvoxamine 50 mg per
day was started as adjunctive treatment, the patient's clozapine level rose from 1146 ng/mL before
fluvoxamine treatment to 2750 ng/mL after 28 days of fluvoxamine treatment. During this time the
patient's compulsive symptoms remained unchanged, but psychotic symptoms worsened. The authors
postulated that the worsening of psychotic symptoms could be due to SSRI inhibition of clozapine
metabolism by cytochrome P450 isozymes, or an imbalance of the serotonergic and dopaminergic
blockade caused by coadministration the two drugs (Chong et al, 1997).
c) Fluvoxamine significantly increased serum levels of clozapine in 16 patients with schizophrenia.
Clozapine 2.5 to 3 mg/kg/day was given for 14 days, then fluvoxamine 50 mg daily was added for 14
days. Serum concentrations of clozapine and two metabolites were measured on days 1, 7, and 14. The
increase in clozapine serum concentration was approximately 3-fold when given with fluvoxamine
compared to clozapine alone (Wetzel et al, 1998).
d) Two patients experienced the onset of extrapyramidal symptoms (EPS) when fluvoxamine was
added to an existing regimen that included clozapine. The first patient, a 46-year-old male, was
stabilized on clozapine 400 mg daily for more than a year when fluvoxamine 25 mg daily was started.
No signs of EPS were present before fluvoxamine therapy, and the clozapine plasma level was 686.2
ng/mL. Four days after fluvoxamine was initiated, the patient experienced rigidity and an Extrapyramidal
Symptom Rating Scale (ESRS) score of 6. Three weeks later, the ESRS had increased to 8 and the
clozapine level was 817.9 ng/mL. Fluvoxamine was discontinued, and the ESRS score and clozapine
level decreased to 1 and 686.8 ng/mL, respectively, three weeks later. The second patient, a 46-yearold female, was maintained on clozapine 600 mg daily for more than two years with a plasma level of
1292.5 ng/mL and no signs of EPS. Fluvoxamine was started at 25 mg daily and six days later she
developed moderate akathisia and tremors (ESRS of 7). Three weeks and six weeks into combination
therapy, her clozapine plasma levels were 1438.2 ng/mL and 1548.9 ng/mL, respectively. The ESRS
increased to 9, but the patient preferred the combination therapy due to the efficacy in alleviating
psychotic symptoms (Kuo et al, 1998).
3.5.1.AJ Cyclosporine
1) Interaction Effect: an increased risk of cyclosporine toxicity (renal dysfunction, cholestasis, paresthesias)
2) Summary: Fluvoxamine was reported to increase cyclosporine trough serum levels in a 62-year-old
female. Fluvoxamine is an inhibitor of cytochrome P450 3A4 enzymes, which are required for cyclosporine
metabolism (Vella & Sayegh, 1998a).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Closely monitor cyclosporine serum concentrations when fluvoxamine therapy is
initiated, altered, or discontinued.
7) Probable Mechanism: inhibition of cytochrome P450 3A4 enzymes by fluvoxamine decreases
cyclosporine metabolism
8) Literature Reports
a) A 62-year-old female received a cadaveric renal allograft nine years prior to initiating fluvoxamine
therapy for depression. Her baseline cyclosporine trough level ranged from 200 ng/mL to 250 ng/mL,
and serum creatinine was 1.5 mg/dL. Medications included cyclosporine 300 mg daily, prednisone,
atenolol, levothyroxine, bumetanide, rocaltrol, and omeprazole. Fluvoxamine 100 mg daily was started
for symptoms of depression, and two weeks later the patient complained of shivering and exhibited a
fine tremor. Cyclosporine trough level was 380 ng/mL and serum creatinine had increased to 1.9 mg/dL.
Cyclosporine dosage was decreased to 200 mg daily, and both the cyclosporine trough level and serum
creatinine returned to their baseline values (Vella & Sayegh, 1998).
3.5.1.AK Dalteparin
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 54
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
55 of 160
Page 55
of 244
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.AL Danaparoid
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 55
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
56 of 160
Page 56
of 244
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.AM Defibrotide
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 56
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
57 of 160
Page 57
of 244
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.AN Dehydroepiandrosterone
1) Interaction Effect: development of manic symptoms
2) Summary: A case has been reported in which concomitant dehydroepiandrosterone (DHEA) and
sertraline use was suggested to precipitate a manic episode in a patient with a history of bipolar disorder
(Dean, 2000a). DHEA was also noted to cause mania in a patient with no previous personal or family history
of bipolar disorder (Markowitz et al, 1999). Elevated DHEA levels have been found in patients with mental
disorders; DHEA suppression has lead to improvement in psychotic symptoms (Howard, 1992). DHEA
possesses proserotonergic activity which may predispose patients to manic episodes (Majewska, 1995).
DHEA is a precursor to androgenic steroids, which in high doses may precipitate mania (Markowitz et al,
1999). Patients taking medication for bipolar disorder or patients with a personal and/or family history of
bipolar disorder should not take DHEA until further data is available to characterize this drug-herb
interaction. Concomitant use of DHEA with selective serotonin reuptake inhibitors (SSRIs) should be
avoided due to the potential additive precipitation of mania.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Avoid concomitant use of dehydroepiandrosterone (DHEA) and selective serotonin
reuptake inhibitors. If patients present with manic symptoms (i.e. agitation, anger, irritability, aggressive
behavior), determine if the patient is using DHEA and discontinue DHEA.
7) Probable Mechanism: serotonergic activity of dehydroepiandrosterone, possibly increased androgen
levels
8) Literature Reports
a) A 31-year-old male was admitted following threats to commit suicide and injure family members. He
had self-initiated sertraline 100 milligrams (mg) daily for the previous 2 to 3 weeks for depression.
Sertraline had been prescribed 3 years prior when he was diagnosed with bipolar disorder, which he
discontinued after 2 weeks. He had also taken dehydroepiandrosterone (DHEA) 300 mg to 500 mg daily
for the previous 2 months apparently for weight training. Following use of DHEA for a short time, he
became more irritable, was not sleeping well, and began threatening a female friend and family
members. He also drank alcohol occasionally and reportedly had difficulty controlling his anger when
intoxicated. Sertraline was stopped and the patient was treated with valproic acid with the dose titrated
to 500 mg twice daily. The combination of DHEA, sertraline, and alcohol was suggested responsible for
the developing of the manic episode (Dean, 2000).
3.5.1.AO Dermatan Sulfate
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 57
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
58 of 160
Page 58
of 244
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.AP Desipramine
1) Interaction Effect: desipramine toxicity (dry mouth, urinary retention, sedation)
2) Summary: While an early report on fluvoxamine combined with desipramine or imipramine found
increased TCA concentrations (Spina et al, 1992a), later studies by the same investigators reported that
fluvoxamine caused no significant alterations in desipramine pharmacokinetics (Spina et al, 1993a; Spina et
al, 1993aa).
3) Severity: minor
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Monitor patients for signs of desipramine and fluvoxamine toxicity; lower doses of
one or both agents may be required with concomitant therapy.
7) Probable Mechanism: decreased desipramine metabolism
8) Literature Reports
a) The addition of fluvoxamine to imipramine or desipramine in four patients was reported to result in
greatly increased tricyclic antidepressant plasma levels (Spina et al, 1992). Three of the four patients
showed signs of tricyclic toxicity.
b) A controlled study in eight depressed patients found a slight, but insignificant, increase in
desipramine concentrations, after 10 days, when fluvoxamine was added to desipramine therapy (Spina
et al, 1993a).
c) A pharmacokinetic study in 12 healthy volunteers reviewed concurrent use of desipramine and
fluvoxamine (Spina et al, 1993). No significant alterations in the pharmacokinetics of either drug were
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 58
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
59 of 160
Page 59
of 244
found.
3.5.1.AQ Desirudin
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.AR Desvenlafaxine
1) Interaction Effect: increased risk of serotonin syndrome (hypertension, hyperthermia, myoclonus, mental
status changes)
2) Summary: Concurrent use of desvenlafaxine and a selective serotonin reuptake inhibitor (SSRI) may
result in serotonin syndrome, which may be life-threatening. Symptoms of serotonin syndrome may include
restlessness, hallucinations, loss of coordination, fast heart beat, rapid changes in blood pressure, increased
body temperature, overreactive reflexes, nausea, vomiting, and diarrhea (Prod Info PRISTIQ(TM) oral
extended-release tablets, 2008).
3) Severity: major
4) Onset: unspecified
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 59
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
60 of 160
Page 60
of 244
5) Substantiation: theoretical
6) Clinical Management: Coadministration of desvenlafaxine and an SSRI may result in a life-threatening
condition called serotonin syndrome. If these agents are used together, discuss the risks of serotonin
syndrome with the patient and monitor closely for symptoms of serotonin syndrome (restlessness,
hyperthermia, hyperreflexia, incoordination), especially during treatment initiation and dose increases (Prod
Info PRISTIQ(TM) oral extended-release tablets, 2008).
7) Probable Mechanism: additive serotonergic effect
3.5.1.AS Dexfenfluramine
1) Interaction Effect: serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes)
2) Summary: Dexfenfluramine is a nonspecific serotonin agonist that both enhances the release of
serotonin and inhibits serotonin reuptake. Combination therapy with dexfenfluramine and another selective
serotonin reuptake inhibitor, such as fluvoxamine, has the potential to cause serotonin syndrome (Schenck
& Mahowald, 1996a). Serotonin syndrome is a hyperserotonergic state characterized by symptoms such as
restlessness, myoclonus, changes in mental status, hyperreflexia, diaphoresis, shivering, and tremor.
Serious, even fatal, reactions have been reported (Sternbach, 1991k). Dexfenfluramine should not be used
in combination with fluvoxamine (Prod Info Redux(R), 1997).
3) Severity: major
4) Onset: rapid
5) Substantiation: theoretical
6) Clinical Management: Concurrent use of dexfenfluramine and fluvoxamine may result in an additive
increase in serotonin levels in the central nervous system, and could result in serotonin syndrome
(hypertension, hyperthermia, myoclonus, mental status changes). Dexfenfluramine should not be used in
combination with fluvoxamine or other serotonin specific reuptake inhibitors.
7) Probable Mechanism: additive serotonergic effects
3.5.1.AT Dexketoprofen
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.AU Diazepam
1) Interaction Effect: diazepam and N-desmethyldiazepam accumulation
2) Summary: Coadministration of fluvoxamine 150 mg daily with a single oral dose of diazepam 10 mg
resulted in a 65% decrease in clearance of diazepam. The clearance of diazepam's primary active
metabolite, N-desmethyldiazepam, is reduced to immeasurable levels. This effect may be more pronounced
with increasing doses of fluvoxamine (Prod Info Luvox(R), 1997g).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Diazepam and fluvoxamine should not be taken concurrently due to the possibility
of significant diazepam accumulation. Consider switching to a benzodiazepine eliminated by glucuronidation
(eg, lorazepam, oxazepam, temazepam) and monitor for signs of benzodiazepine intoxication (eg, sedation,
dizziness, ataxia, weakness, decreased cognition or motor performance).
7) Probable Mechanism: reduced diazepam clearance
3.5.1.AV Diclofenac
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 60
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
61 of 160
Page 61
of 244
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.AW Dicumarol
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 61
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
62 of 160
Page 62
of 244
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.AX Diflunisal
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.AY Dihydroergotamine
1) Interaction Effect: an increased risk of ergotism (nausea, vomiting, vasospastic ischemia)
2) Summary: Because of the potential for serious toxicity including vasospasm that can occur with
increased plasma concentrations of ergot derivatives, the concurrent use of fluvoxamine and ergot
derivatives is contraindicated. Fluvoxamine and ergot derivatives are both metabolized by cytochrome P450
3A4 enzymes, and the competition for metabolism could result in an increased plasma concentration of the
ergot derivative (Prod Info Cafergot(R), 2002).
3) Severity: contraindicated
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: The concurrent use of fluvoxamine and ergot derivatives is contraindicated.
7) Probable Mechanism: inhibition of cytochrome P450 3A4- mediated ergot metabolism by fluvoxamine
3.5.1.AZ Diltiazem
1) Interaction Effect: bradycardia
2) Summary: Fluvoxamine may inhibit the metabolism of diltiazem, causing elevated diltiazem levels and
bradycardia (Prod Info Luvox(R), 1997s).
3) Severity: minor
4) Onset: rapid
5) Substantiation: theoretical
6) Clinical Management: Monitor patients for appropriate cardiovascular response to calcium channel
blockade, with dose titration as required to achieve desired effect.
7) Probable Mechanism: decreased diltiazem metabolism
3.5.1.BA Dipyridamole
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and antiplatelet agents has been associated
with an increased risk of bleeding. Bleeding events reported have included epistaxis, ecchymosis,
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 62
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
63 of 160
Page 63
of 244
hematoma, petechiae, and life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008;
Prod Info PROZAC(R) oral capsules, delayed-release capsules, solution, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an antiplatelet agent are given concurrently, monitor patient for
signs of increased bleeding (Prod Info PAXIL(R) oral tablets, suspension, 2008; Prod Info PROZAC(R) oral
capsules, delayed-release capsules, solution, 2008)
7) Probable Mechanism: unknown
3.5.1.BB Dipyrone
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.BC Droperidol
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Any drug known to have the potential to prolong the QT interval should not be used together
with droperidol. Possible pharmacodynamic interactions can occur between droperidol and potentially
arrhythmogenic agents such as antidepressants that prolong the QT interval (Prod Info Inapsine(R), 2002).
3) Severity: major
4) Onset: rapid
5) Substantiation: theoretical
6) Clinical Management: Droperidol should be administered with extreme caution in the presence of risk
factors for development of prolonged QT syndrome, such as treatment with antidepressants.
7) Probable Mechanism: additive cardiac effects
3.5.1.BD Droxicam
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 63
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
64 of 160
Page 64
of 244
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.BE Duloxetine
1) Interaction Effect: increased duloxetine bioavailability and an increased risk of serotonin syndrome
2) Summary: Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) that is
primarily metabolized by the CYP1A2 and CYP2D6 isozymes. The concomitant use of duloxetine with
fluvoxamine, a SSRI, is not recommended due to the potential for serotonin syndrome. In addition,
coadministration of fluvoxamine 100 mg (a CYP1A2 inhibitor) with duloxetine 40 mg twice a day in 14
CYP2D6 poor metabolizer subjects resulted in a 6-fold increase in duloxetine AUC and Cmax. Also, when
14 male patients were given duloxetine 60 mg together with fluvoxamine 100 mg, duloxetine AUC, Cmax,
and half-life increased by 6-fold, about 2.5-fold, and 3-fold, respectively (Prod Info CYMBALTA(R) delayedrelease oral capsules, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: established
6) Clinical Management: The concomitant use of duloxetine and fluvoxamine is not recommended due to
the potential for development of serotonin syndrome. Additionally, concomitant use has resulted in
significantly increased duloxetine exposure and serum levels (Prod Info CYMBALTA(R) delayed-release oral
capsules, 2008).
7) Probable Mechanism: inhibition of CYP1A2-mediated duloxetine metabolism; additive serotonergic
effects
3.5.1.BF Eletriptan
1) Interaction Effect: an increased risk of serotonin syndrome
2) Summary: There have been case reports of weakness, hyperreflexia, and incoordination following
concomitant use of sumatriptan, a 5-hydroxytryptamine-1 (5HT-1) agonist, and a serotonin specific reuptake
inhibitor (SSRI) (Prod Info Imitrex(R) Nasal Spray, 2003). Because eletriptan is a 5HT 1B/1D agonist, a
similar interaction between SSRIs and eletriptan may occur (Prod Info Relpax(R), 2003). Concurrent use of
a triptan and an SSRI may result in serotonin syndrome which may be life-threatening. Symptoms of
serotonin syndrome may include restlessness, hallucinations, loss of coordination, fast heart beat, rapid
changes in blood pressure, increased body temperature, overreactive reflexes, nausea, vomiting, and
diarrhea. Clinicians should be aware that triptans may be commonly used intermittently and that either the
triptan or the SSRI may be prescribed by a different physician. Discuss the risks of serotonin syndrome with
patients who are prescribed this combination and monitor them closely for symptoms of serotonin syndrome
(US Food and Drug Administration, 2006).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Coadministration of a triptan, such as eletriptan, and an SSRI may result in a lifethreatening condition called serotonin syndrome. Be aware that triptans may be commonly used
intermittently and that either the triptan or the SSRI may be prescribed by a different physician. If these
agents are used together, discuss the risks of serotonin syndrome with the patient and monitor closely for
symptoms of serotonin syndrome (restlessness, hyperthermia, hyperreflexia, incoordination).
7) Probable Mechanism: additive pharmacologic effects resulting in excessive serotonergic stimulation
3.5.1.BG Eltrombopag
1) Interaction Effect: increased eltrombopag plasma concentrations
2) Summary: Concomitant use of eltrombopag and fluvoxamine, a strong CYP1A2 inhibitor, may result in
elevated eltrombopag plasma concentrations due to inhibition of CYP1A2-mediated eltrombopag
metabolism. The patient should be monitored for excessive eltrombopag exposure when eltrombopag and
fluvoxamine are coadministered (Prod Info PROMACTA(R) oral tablets, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Concomitant use of eltrombopag and fluvoxamine, a strong CYP1A2 inhibitor, may
result in elevated eltrombopag plasma concentrations. Monitor the patient for excessive eltrombopag
exposure when eltrombopag and fluvoxamine are coadministered (Prod Info PROMACTA(R) oral tablets,
2008).
7) Probable Mechanism: inhibition of CYP1A2-mediated eltrombopag metabolism by fluvoxamine
3.5.1.BH Enoxaparin
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 64
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
65 of 160
Page 65
of 244
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.BI Epoprostenol
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and antiplatelet agents has been associated
with an increased risk of bleeding. Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008;
Prod Info PROZAC(R) oral capsules, delayed-release capsules, solution, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an antiplatelet agent are given concurrently, monitor patient for
signs of increased bleeding (Prod Info PAXIL(R) oral tablets, suspension, 2008; Prod Info PROZAC(R) oral
capsules, delayed-release capsules, solution, 2008)
7) Probable Mechanism: unknown
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 65
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
66 of 160
Page 66
of 244
3.5.1.BJ Eptifibatide
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and antiplatelet agents has been associated
with an increased risk of bleeding. Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008;
Prod Info PROZAC(R) oral capsules, delayed-release capsules, solution, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an antiplatelet agent are given concurrently, monitor patient for
signs of increased bleeding (Prod Info PAXIL(R) oral tablets, suspension, 2008; Prod Info PROZAC(R) oral
capsules, delayed-release capsules, solution, 2008)
7) Probable Mechanism: unknown
3.5.1.BK Ergoloid Mesylates
1) Interaction Effect: an increased risk of ergotism (nausea, vomiting, vasospastic ischemia)
2) Summary: Because of the potential for serious toxicity including vasospasm that can occur with
increased plasma concentrations of ergot derivatives, the concurrent use of fluvoxamine and ergot
derivatives is contraindicated. Fluvoxamine and ergot derivatives are both metabolized by cytochrome P450
3A4 enzymes, and the competition for metabolism could result in an increased plasma concentration of the
ergot derivative (Prod Info Cafergot(R), 2002).
3) Severity: contraindicated
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: The concurrent use of fluvoxamine and ergot derivatives is contraindicated.
7) Probable Mechanism: inhibition of cytochrome P450 3A4- mediated ergot metabolism by fluvoxamine
3.5.1.BL Ergonovine
1) Interaction Effect: an increased risk of ergotism (nausea, vomiting, vasospastic ischemia)
2) Summary: Because of the potential for serious toxicity including vasospasm that can occur with
increased plasma concentrations of ergot derivatives, the concurrent use of fluvoxamine and ergot
derivatives is contraindicated. Fluvoxamine and ergot derivatives are both metabolized by cytochrome P450
3A4 enzymes, and the competition for metabolism could result in an increased plasma concentration of the
ergot derivative (Prod Info Cafergot(R), 2002).
3) Severity: contraindicated
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: The concurrent use of fluvoxamine and ergot derivatives is contraindicated.
7) Probable Mechanism: inhibition of cytochrome P450 3A4- mediated ergot metabolism by fluvoxamine
3.5.1.BM Ergotamine
1) Interaction Effect: an increased risk of ergotism (nausea, vomiting, vasospastic ischemia)
2) Summary: Because of the potential for serious toxicity including vasospasm that can occur with
increased plasma concentrations of ergot derivatives, the concurrent use of fluvoxamine and ergot
derivatives is contraindicated. Fluvoxamine and ergot derivatives are both metabolized by cytochrome P450
3A4 enzymes, and the competition for metabolism could result in an increased plasma concentration of the
ergot derivative (Prod Info Cafergot(R), 2002).
3) Severity: contraindicated
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: The concurrent use of fluvoxamine and ergot derivatives is contraindicated.
7) Probable Mechanism: inhibition of cytochrome P450 3A4- mediated ergot metabolism by fluvoxamine
3.5.1.BN Estazolam
1) Interaction Effect: increased estazolam plasma concentrations and risk of estazolam toxicity
2) Summary: Fluvoxamine is a inhibitor of CYP3A and estazolam metabolism is catalyzed by CYP3A,
therefore fluvoxamine is expected to increase plasma estazolam concentration resulting in an increased risk
of estazolam toxicity and associated adverse effects (Prod Info ProSom(TM), 2004).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Monitor for signs of benzodiazepine intoxication (eg, sedation, dizziness, ataxia,
weakness, decreased cognition or motor performance). If symptoms are present, reduce estazolam dose or
consider switching to a benzodiazepine eliminated by glucuronidation (eg, lorazepam, oxazepam,
temazepam).
7) Probable Mechanism: fluvoxamine inhibition of P450-3A isoform-mediated estazolam metabolism
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 66
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
67 of 160
Page 67
of 244
3.5.1.BO Etodolac
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.BP Etofenamate
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.BQ Etoricoxib
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 67
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
68 of 160
Page 68
of 244
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.BR Felbinac
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.BS Fenbufen
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.BT Fenfluramine
1) Interaction Effect: serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes)
2) Summary: Fenfluramine is a nonspecific serotonin agonist that both enhances the release of serotonin
and inhibits serotonin reuptake. Combination therapy with fenfluramine and another selective serotonin
reuptake inhibitor, such as fluvoxamine, has the potential to cause serotonin syndrome (Schenck &
Mahowald, 1996). Serotonin syndrome is a hyperserotonergic state characterized by symptoms such as
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 68
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
69 of 160
Page 69
of 244
restlessness, myoclonus, changes in mental status, hyperreflexia, diaphoresis, shivering, and tremor.
Serious, even fatal, reactions have been reported (Sternbach, 1991j). Until more data are available,
fenfluramine should not be used in combination with fluvoxamine.
3) Severity: major
4) Onset: rapid
5) Substantiation: theoretical
6) Clinical Management: Concurrent use of fenfluramine and fluvoxamine may result in an additive increase
in serotonin levels in the central nervous system, and could result in serotonin syndrome (hypertension,
hyperthermia, myoclonus, mental status changes). Fenfluramine should not be used in combination with
fluvoxamine or other serotonin specific reuptake inhibitors.
7) Probable Mechanism: additive serotonergic effects
3.5.1.BU Fenoprofen
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.BV Fentiazac
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.BW Floctafenine
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 69
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
70 of 160
Page 70
of 244
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.BX Flufenamic Acid
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.BY Flurbiprofen
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 70
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
71 of 160
Page 71
of 244
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.BZ Fondaparinux
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.CA Fosphenytoin
1) Interaction Effect: an increased risk of phenytoin toxicity (ataxia, hyperreflexia, nystagmus, tremors)
2) Summary: Fosphenytoin is a prodrug of phenytoin and the same interactions that occur with phenytoin
are expected to occur with fosphenytoin (Prod Info Cerebyx(R), 1999). Fluvoxamine inhibits several of the
isoenzymes of the cytochrome P450 enzyme system (oxidative metabolism); IA2, IIC9, and IIIA4. Since
phenytoin is eliminated at least partially via the CYP450 IIC9 pathway, it is possible that coadministration
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 71
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
72 of 160
Page 72
of 244
with fluvoxamine may cause elevations in phenytoin plasma levels (Prod Info Luvox(R), 1997t). During an in
vitro study, the inhibitory effects of fluvoxamine on cytochrome P450 2C9 were evaluated using phydroxylation of phenytoin as an established index reaction reflecting CYP2C9 activity. In vivo, phydroxylation of phenytoin depends on the formation of 5-(p-hydroxy-phenyl)-5-phenylhydantoin (HPPH).
Fluvoxamine, a strong inhibitor of HPPH, impaired the formation of HPPH, which can lead to an increase in
steady-state phenytoin levels (Schmider et al, 1997a).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Consideration should be given to monitoring of phenytoin serum levels when
fluvoxamine is added or withdrawn from therapy and dosage adjustments made accordingly. Patients should
be counseled to be aware of the potential side effects of phenytoin toxicity such as drowsiness, ataxia, and
nystagmus, and to notify their physician if such side effects occur.
7) Probable Mechanism: decreased oxidative metabolism
3.5.1.CB Frovatriptan
1) Interaction Effect: an increased risk of serotonin syndrome
2) Summary: There have been case reports of weakness, hyperreflexia, and incoordination following
concomitant use of sumatriptan, a 5-hydroxytryptamine-1 (5HT-1) agonist, and a serotonin specific reuptake
inhibitor (SSRI) (Prod Info Imitrex(R) Nasal Spray, 2003). Because frovatriptan is a 5HT 1B/1D agonist, a
similar interaction between SSRIs and frovatriptan may occur (Prod Info Frova(R), 2004). Concurrent use of
frovatriptan and an SSRI may result in serotonin syndrome which may be life-threatening. Symptoms of
serotonin syndrome may include restlessness, hallucinations, loss of coordination, fast heart beat, rapid
changes in blood pressure, increased body temperature, overreactive reflexes, nausea, vomiting, and
diarrhea. Clinicians should be aware that triptans may be commonly used intermittently and that either the
triptan or the SSRI may be prescribed by a different physician. Discuss the risks of serotonin syndrome with
patients who are prescribed this combination and monitor them closely for symptoms of serotonin syndrome
(US Food and Drug Administration, 2006).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Coadministration of a triptan, such as frovatriptan, and an SSRI may result in a
life-threatening condition called serotonin syndrome. Be aware that triptans may be commonly used
intermittently and that either the triptan or the SSRI may be prescribed by a different physician. If these
agents are used together, discuss the risks of serotonin syndrome with the patient and monitor closely for
symptoms of serotonin syndrome (restlessness, hyperthermia, hyperreflexia, incoordination).
7) Probable Mechanism: additive pharmacologic effects resulting in excessive serotonergic stimulation
3.5.1.CC Furazolidone
1) Interaction Effect: weakness, hyperreflexia, and incoordination
2) Summary: Although not its primary mechanism of action, furazolidone has monoamine oxidase inhibitor
activity. Cases of serious sometimes fatal reactions have been reported in patients receiving selective
serotonin reuptake inhibitors (SSRI) in combination with monoamine oxidase inhibitors (MAOIs).
Hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and
mental status changes that include extreme agitation progressing to delirium and coma have been reported.
Furazolidone should not be used in combination with an SSRI, or within a minimum of 14 days of
discontinuing therapy with a MAOI (Prod Info Furoxone(R), 1999).
3) Severity: contraindicated
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: If concurrent therapy with furazolidone and a selective serotonin reuptake inhibitor
(SSRI) is deemed to be necessary, closely monitor the patient for signs of serotonergic excess (mental
status changes, diaphoresis, fever, weakness, hyperreflexia, incoordination).
7) Probable Mechanism: additive pharmacologic effects resulting in excessive serotonergic stimulation
3.5.1.CD Galantamine
1) Interaction Effect: increased galantamine plasma concentrations
2) Summary: Based upon in vitro studies, the major enzymes involved in galantamine metabolism are
CYP3A4 and CYP2D6. Fluvoxamine is a known inhibitor of CYP2D6. In a population pharmacokinetic
analysis using a database of 852 Alzheimer's disease patients, several drugs which inhibit CYP2D6,
including fluvoxamine (N=14), demonstrated a 25-33% decrease in galantamine clearance. The resulting
plasma concentration increase of galantamine may warrant caution when it is coadministered with
fluvoxamine. Monitor for galantamine toxicity including anorexia, nausea, vomiting, dizziness, arrhythmias or
gastrointestinal bleeding (Prod Info RAZADYNE(R) ER extended release oral capsules, oral tablets, oral
solution, 2007).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 72
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
73 of 160
Page 73
of 244
6) Clinical Management: Increased galantamine plasma concentrations may result from fluvoxamine
inhibition of galantamine CYP2D6-mediated metabolism. Monitor for galantamine toxicity including anorexia,
nausea, vomiting, dizziness, arrhythmias, or gastrointestinal bleeding (Prod Info RAZADYNE(R) ER
extended release oral capsules, oral tablets, oral solution, 2007).
7) Probable Mechanism: inhibition of cytochrome CYP2D6-mediated galantamine metabolism
3.5.1.CE Ginkgo
1) Interaction Effect: increased risk of serotonin syndrome (hypertension, hyperthermia, myoclonus, mental
status changes)
2) Summary: The addition of Ginkgo biloba and/or St. John's Wort to therapy with buspirone and fluoxetine
may have precipitated a hypomanic episode in a case report (Spinella & Eaton, 2002a). It is unclear if
Ginkgo or St. John's Wort, the combination of both, or other patient factors, contributed to the effect.
Theoretically, Ginkgo may increase the risk of serotonin syndrome when taken with selective serotonin
reuptake inhibitors (SSRIs). Caution is advised, especially when ginkgo is taken to counteract sexual
dysfunction associated with SSRIs. Ginkgo may inhibit monoamine oxidase (Sloley et al, 2000; White et al,
1996), and has demonstrated serotonergic activity in animals (Ramassamy et al, 1992) which might
increase the risk of serotonin syndrome when ginkgo is combined with SSRIs. The potential MAO inhibitory
activity of ginkgo is questionable. A human study did not show MAO inhibition in the brain following oral
consumption (Fowler et al, 2000). Ginkgo biloba extract inhibited MAO-A/MAO-B in the rat brain in vitro
(Sloley et al, 2000; White et al, 1996) and MAO-B in human platelets in vitro (White et al, 1996). No
significant MAO inhibition was found in mice following oral consumption (Porsolt et al, 2000).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Monitor patients closely for symptoms of serotonin syndrome if ginkgo is combined
with selective serotonin reuptake inhibitors (SSRIs).
7) Probable Mechanism: additive pharmacologic effects resulting in excessive serotonergic stimulation
8) Literature Reports
a) A 42-year-old female experienced symptoms consistent with a mixed hypomanic episode following
concomitant use of fluoxetine, buspirone, Ginkgo biloba, and St. John's Wort. The symptoms resolved
following discontinuation of Ginkgo and St. John's Wort. The patient was being treated for depression
following a mild traumatic brain injury with fluoxetine 20 milligrams (mg) twice daily and buspirone 15
mg twice daily. Several weeks prior to presentation, buspirone was increased to 20 mg twice daily for
persistent anxiety and the patient began taking Ginkgo biloba, melatonin, and St. John's Wort in
unspecified doses. Melatonin was considered unlikely to have contributed to her symptoms. Ginkgo and
St. John's Wort were considered possible contributors since they may potentiate antidepressants, and
considering the temporal relationship between the use of the herbs and onset of symptoms and
discontinuation of the herbs and resolution of symptoms. However, the brain injury was considered a
possible contributor (Spinella & Eaton, 2002).
3.5.1.CF Glimepiride
1) Interaction Effect: an increase in plasma concentrations of glimepiride
2) Summary: Caution is advised when fluvoxamine is coadministered with glimepiride. An increase in
plasma concentrations of glimepiride has been documented in healthy patients when used concomitantly
with fluvoxamine without a significant effect on blood glucose concentrations (Niemi et al, 2001).
3) Severity: minor
4) Onset: rapid
5) Substantiation: established
6) Clinical Management: Use glimepiride and fluvoxamine concomitantly with caution or use therapeutic
alternative. Monitor the patient for hypoglycemia if used concurrently.
7) Probable Mechanism: inhibition of the metabolism of glimepiride through the cytochrome P450 2C9
enzyme
8) Literature Reports
a) Plasma concentrations of glimepiride were moderately increased when used concomitantly with
fluvoxamine. A double-blind, randomized, crossover study with three phases including a 4-week
washout period between the phases was conducted in twelve healthy volunteers. The aim of the study
is to investigate the effects of fluvoxamine on the pharmacokinetics and pharmacodynamics of
glimepiride. Subjects received fluvoxamine 100 mg or placebo orally once daily for 4 days. On day 4, a
single oral dose of 0.5 mg of glimepiride was administered after the patients fasted overnight. Meals
were served 15 minutes after, 3 hours after, and 7 hours after glimepiride administration. For the
fluvoxamine phase, the peak concentration (Cmax) was 143% (p less than 0.05) of the respective
placebo value, and the half-life was increased from 2 to 2.3 hours (p less than 0.01). The increase in the
area under the concentration-time curve (AUC) was not significant, and differences in blood glucose
levels were not statistically significant (Niemi et al, 2001).
3.5.1.CG Guarana
1) Interaction Effect: symptoms of excessive caffeine (insomnia, headache, restlessness, nervousness,
palpitations, and arrhythmias)
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 73
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
74 of 160
Page 74
of 244
2) Summary: The primary pharmacologically-active ingredient of guarana is caffeine. Fluvoxamine inhibits
CYP1A2 and CYP2D6 which are responsible for caffeine metabolism. Decreased caffeine clearance and
increased half-life have been demonstrated in humans. Signs and symptoms of caffeine excess may result if
the compounds are taken together. Patients should avoid guarana use during therapy with fluvoxamine in
order to avoid complications (Jeppesen et al, 1996c).
3) Severity: moderate
4) Onset: rapid
5) Substantiation: theoretical
6) Clinical Management: Patients should be advised of the caffeine content of guarana, and of symptoms of
excess if taken with fluvoxamine (insomnia, headache, restlessness, nervousness, palpitations, and
arrhythmias) as well as symptoms of caffeine withdrawal which may accompany abrupt discontinuation of
guarana (headache, fatigue, depression, anxiety, and insomnia). Patients should avoid guarana use during
therapy with fluvoxamine in order to avoid complications.
7) Probable Mechanism: fluvoxamine may inhibit the metabolism of the caffeine content of guarana
8) Literature Reports
a) In an open, randomized, cross-over study of 8 volunteers, fluvoxamine significantly decreased
caffeine total clearance and increased caffeine half-life. Fluvoxamine was administered as 50 milligrams
(mg) for 4 days, then 100 mg for 8 days while subjects abstained from all caffeine intake. Caffeine 200
mg was then administered orally. Total clearance of caffeine decreased from 107 milliliters/minute
(ml/min) to 21 ml/min, and half-life increased from 5 hours to 31 hours. Patients taking fluvoxamine
should restrict caffeine intake (Jeppesen et al, 1996b).
b) In vitro, fluvoxamine was found to be a very potent inhibitor of the formation of N-demethylated
caffeine metabolites with K1 values of 0.08 micromoles (mcmol) to 0.28 mcmol. The formation of 1,7dimethylxanthine was abolished by 10 mcmol of fluvoxamine, implying the N3-demethylation of caffeine
is almost entirely catalyzed by CYP1A2 (Rasmussen et al, 1998a).
c) At least 14 metabolites are formed from caffeine whose main route of elimination is N3demethylation to paraxanthine (1,7-methylxanthine) which accounts for greater than 80% of caffeine
elimination (Lelo et al, 1986a).
d) CYP1A2 is the major enzyme metabolizing caffeine to 1,7-dimethylxanthine (Berthou et al, 1991a;
Sesardic et al, 1990a; Butler et al, 1989a). CYP1A2 is also a major enzyme in the formation of 3,7dimethylxanthine and 1,3-dimethylxantihine from caffeine (Gu et al, 1992a; Berthou et al, 1991a; Grant
et al, 1987a).
3.5.1.CH Haloperidol
1) Interaction Effect: an increased risk of haloperidol toxicity
2) Summary: Haloperidol serum concentrations were increased by the coadministration of fluvoxamine in a
small double blind, randomized, placebo controlled, crossover study (Daniel et al, 1994a).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Caution should be used when fluvoxamine is administered with haloperidol.
Monitor serum concentrations of haloperidol and adjust the dose accordingly. Also monitor the patient for
signs and symptoms of worsening clinical and cognitive assessments.
7) Probable Mechanism: inhibition of cytochrome P450-mediated metabolism of haloperidol
8) Literature Reports
a) Four inpatient males with chronic schizophrenia were stabilized on haloperidol and benztropine
orally. In randomized order, the patients were then placed on fluvoxamine for six weeks or identically
appearing placebo. Results showed that the addition of fluvoxamine to haloperidol therapy significantly
elevated serum concentrations of haloperidol. In addition, haloperidol concentrations did not plateau
during the six-week period of fluvoxamine treatment, indicating that the haloperidol concentrations may
have continued to increase at a constant dose of fluvoxamine. The coadministration of haloperidol and
fluvoxamine also worsened all measures of clinical and cognitive function assessments, including
delayed recall memory and attentional function. It is possible that haloperidol may require the
cytochrome P450 1A2 system for metabolism, and fluvoxamine is known to be a potent inhibitor of this
enzyme pathway (Daniel et al, 1994).
3.5.1.CI Heparin
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 74
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
75 of 160
Page 75
of 244
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.CJ Hydroxytryptophan
1) Interaction Effect: an increased risk of serotonin syndrome (hypertension, hyperthermia, myoclonus,
mental status changes)
2) Summary: Hydroxytryptophan (5-HTP) may potentiate the serotonergic effect of selective serotonin
reuptake inhibitors (SSRIs) (Meltzer et al, 1997a). Since 5-HTP increases serotonin levels, when combined
with an SSRI, the serotonin level may be increased sufficiently to produce serotonin syndrome. Caution is
advised with concomitant use of 5-HTP and SSRIs.
3) Severity: moderate
4) Onset: rapid
5) Substantiation: theoretical
6) Clinical Management: No cases have been reported of serotonin syndrome resulting from this
combination. Caution is advised if hydroxytryptophan (5-HTP) and a selective serotonin reuptake inhibitor
(SSRI) are used concomitantly. Monitor the patient for early signs of serotonin syndrome such as anxiety,
confusion, and disorientation.
7) Probable Mechanism: additive serotonergic effect
8) Literature Reports
a) Hydroxytryptophan (5-HTP) (200 milligrams (mg) orally) as a single dose increased plasma cortisol
and prolactin levels in both medicated and unmedicated patients with major depression or obsessive
compulsive disorder (OCD). These responses were greater if the patient was also taking fluoxetine (n =
16) (p less than 0.0001). Mean fluoxetine dose for depressed patients was 44 mg/day,and for OCD
patients it was 60 mg/day. Cortisol or prolactin (PRL) levels in patients taking 5-HTP with tricyclic
antidepressants (n = 14) or those receiving no medication (n = 83) were not significantly different from
each other. A measurement of serotonergic effects of antidepressants can be evaluated by measuring
hypothalamic-pituitary-adrenal (HPA) axis or PRL response. No clinical manifestations of serotonin
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 75
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
76 of 160
Page 76
of 244
syndrome were reported in patients taking 5-HTP concomitantly with fluoxetine (Meltzer et al, 1997).
3.5.1.CK Ibuprofen
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.CL Iloprost
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and antiplatelet agents has been associated
with an increased risk of bleeding. Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008;
Prod Info PROZAC(R) oral capsules, delayed-release capsules, solution, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an antiplatelet agent are given concurrently, monitor patient for
signs of increased bleeding (Prod Info PAXIL(R) oral tablets, suspension, 2008; Prod Info PROZAC(R) oral
capsules, delayed-release capsules, solution, 2008)
7) Probable Mechanism: unknown
3.5.1.CM Imipramine
1) Interaction Effect: imipramine toxicity (dry mouth, urinary retention, sedation)
2) Summary: Addition of fluvoxamine to imipramine or desipramine therapy can result in significantly
increased tricyclic antidepressant plasma levels and signs of tricyclic toxicity (Spina et al, 1992c; Spina et al,
1993ac; Spina et al, 1993c). Fluvoxamine significantly increases imipramine half-life and reduces clearance
(Spina et al, 1993c). The addition of fluvoxamine to imipramine or desipramine therapy may result in greatly
increased tricyclic antidepressant plasma levels and tricyclic toxicity (Spina et al, 1992c; Spina et al,
1993ac). A bidirectional effect is suggested, in which fluvoxamine increases imipramine concentrations (by
interfering with N-demethylation), and imipramine increases fluvoxamine levels (Hartter et al, 1993e).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Monitor patients for signs of imipramine and fluvoxamine toxicity; lower doses of
one or both agents may be required with concomitant therapy.
7) Probable Mechanism: decreased imipramine metabolism
8) Literature Reports
a) The pharmacokinetics of combined imipramine and fluvoxamine were studied in healthy volunteers
(Spina et al, 1993b). After a 7-day course of fluvoxamine, imipramine half-life was significantly
increased (from 23 to 41 hours) and clearance decreased (from 1.02 to 0.28 L/h/kg).
b) The addition of fluvoxamine to imipramine or desipramine in four patients was reported to result in
greatly increased tricyclic antidepressant plasma levels (Spina et al, 1992b). Three of four patients
showed signs of tricyclic toxicity. The effect of fluvoxamine 100 mg daily for 10 days on plasma
concentrations of imipramine was studied in seven depressed patients on maintenance therapy (Spina
et al, 1993ab). Imipramine plasma levels were three to four times higher during fluvoxamine
coadministration. One patient complained of anticholinergic effects, along with tremor and confusion.
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 76
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
77 of 160
Page 77
of 244
The mechanism of this drug interaction was inhibition of demethylation of imipramine. A
pharmacokinetic study in healthy volunteers demonstrated a significantly increased imipramine half-life
and reduced clearance (Spina et al, 1993b).
c) Metabolism of tricyclic antidepressants coadministered with fluvoxamine was studied in eight
depressed patients (two patients received imipramine) (Hartter et al, 1993d). Fluvoxamine was found to
interfere with N-demethylation of imipramine. The combination of fluvoxamine and imipramine led to
increased plasma levels of imipramine and decreased concentrations of the N-demethylated imipramine
metabolite desimipramine. In addition, TCA-fluvoxamine coadministration apparently raised plasma
levels of fluvoxamine.
3.5.1.CN Indomethacin
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.CO Indoprofen
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.CP Iproniazid
1) Interaction Effect: CNS toxicity or serotonin syndrome (hypertension, hyperthermia, myoclonus, mental
status changes)
2) Summary: Concurrent administration or overlapping therapy with fluvoxamine and a monoamine oxidase
(MAO) inhibitor may result in CNS toxicity or serotonin syndrome, a hyperserotonergic state characterized
by symptoms such as restlessness, myoclonus, changes in mental status, hyperreflexia, diaphoresis,
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 77
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
78 of 160
Page 78
of 244
shivering, and tremor. Serious, even fatal, reactions have been reported with concomitant use of selective
serotonin reuptake inhibitors and MAO inhibitors (Prod Info Luvox(R), 1997f; Lappin & Auchincloss, 1994c;
Graber et al, 1994c; Suchowersky & de Vries, 1990c). Concomitant use is not recommended.
3) Severity: major
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Concurrent use of fluvoxamine and a MAO inhibitor should be avoided. Wait at
least two weeks after discontinuing an MAO inhibitor before initiating therapy with fluvoxamine. Wait at least
two weeks after discontinuing fluvoxamine before initiating therapy with a MAO inhibitor.
7) Probable Mechanism: serotonin reuptake inhibition
8) Literature Reports
a) Concomitant use of serotonin specific reuptake inhibitors and monoamine oxidase inhibitors can
produce a toxic reaction known as serotonin syndrome (Sternbach, 1991c). Serotonin syndrome is a
condition of serotonergic hyperstimulation and manifests as restlessness, myoclonus, changes in
mental status, hyperreflexia, diaphoresis, shivering, and tremor. If the syndrome is not recognized and
correctly treated, death can result.
b) A 26-year old woman who had been taking isocarboxazid for eight weeks stopped taking the drug
for 11 days before beginning therapy with sertraline. After a single 100 mg sertraline dose, the patient
became restless and developed leg twitches. The patients was later admitted to the emergency room
with diaphoresis, tachycardia, hyperreflexia, and various neuromuscular disturbances. After treatment
with diazepam and propranolol the patient did not improve. The patient was then given two 4 mg doses
of cyproheptadine an hour apart, with notable improvement in symptoms after the second dose (Lappin
& Auchincloss, 1994b).
c) A drug interaction occurred in a 61-year old woman whose regimen of sertraline 100 mg twice daily
was added to a regimen of lithium, phenelzine, thioridazine, and doxepin. Three hours after taking the
first sertraline dose, the patient was found in a semicomatose state, with elevated body temperature,
increased pulse, increased respiration rate, and a blood pressure of 140/110 mm Hg. After
transportation to the hospital, the patient was misdiagnosed as having neuroleptic malignant syndrome
(NMS) which was later changed to serotonin syndrome due to a reaction between sertraline and
phenelzine. The authors suggest that monoamine oxidase inhibitor (MAOI) therapy should be
discontinued for at least two weeks before initiation of therapy with a selective serotonin reuptake
inhibitor (SSRI) and that before starting a MAOI, SSRI therapy should be discontinued for at least five
half-lives of the parent drug and any active metabolites (Graber et al, 1994b).
d) Two cases reports suggested a possible interaction between fluoxetine and selegiline (Suchowersky
& de Vries, 1990b). One case involved a first episode of mania being observed approximately one
month after adding selegiline to fluoxetine therapy. The patient improved two months after both drugs
were discontinued, and no further details were provided. The second case involved diaphoresis,
vasoconstriction, and cyanosis of the hands which occurred in close temporal relationship to adding
fluoxetine and selegiline. Both drugs were discontinued, with relatively quick resolution of symptoms.
Rechallenge with fluoxetine alone occurred without incident.
3.5.1.CQ Isocarboxazid
1) Interaction Effect: CNS toxicity or serotonin syndrome (hypertension, hyperthermia, myoclonus, mental
status changes)
2) Summary: Concurrent administration or overlapping therapy with fluvoxamine and a monoamine oxidase
(MAO) inhibitor may result in CNS toxicity or serotonin syndrome, a hyperserotonergic state characterized
by symptoms such as restlessness, myoclonus, changes in mental status, hyperreflexia, diaphoresis,
shivering, and tremor. Serious, even fatal, reactions have been reported with concomitant use of serotonin
specific reuptake inhibitors and MAO inhibitors (Prod Info Luvox(R), 1997z; Lappin & Auchincloss, 1994s;
Graber et al, 1994s; Suchowersky & de Vries, 1990s). Concomitant use is contraindicated (Prod Info
Marplan(R), 1998).
3) Severity: contraindicated
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Concurrent use of fluvoxamine and isocarboxazid is contraindicated. Wait at least
two weeks after discontinuing isocarboxazid before initiating therapy with fluvoxamine. Wait at least two
weeks after discontinuing fluvoxamine before initiating therapy with isocarboxazid.
7) Probable Mechanism: serotonin reuptake inhibition
8) Literature Reports
a) Concomitant use of serotonin specific reuptake inhibitors and monoamine oxidase inhibitors can
produce a toxic reaction known as serotonin syndrome (Sternbach, 1991m). Serotonin syndrome is a
condition of serotonergic hyperstimulation and manifests as restlessness, myoclonus, changes in
mental status, hyperreflexia, diaphoresis, shivering, and tremor. If the syndrome is not recognized and
correctly treated, death can result.
b) A 26-year old woman who had been taking isocarboxazid for eight weeks stopped taking the drug
for 11 days before beginning therapy with sertraline. After a single 100 mg sertraline dose, the patient
became restless and developed leg twitches. The patients was later admitted to the emergency room
with diaphoresis, tachycardia, hyperreflexia, and various neuromuscular disturbances. After treatment
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 78
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
79 of 160
Page 79
of 244
with diazepam and propranolol the patient did not improve. The patient was then given two 4 mg doses
of cyproheptadine an hour apart, with notable improvement in symptoms after the second dose (Lappin
& Auchincloss, 1994r).
c) A drug interaction was reported in a 61-year old woman in which sertraline 100 mg twice daily was
added to a regimen of lithium, phenelzine, thioridazine, and doxepin. Three hours after taking the first
sertraline dose, the patient was found in a semicomatose state, with elevated body temperature,
increased pulse, increased respiration rate, and a blood pressure of 140/110 mm Hg. After
transportation to the hospital, the patient was misdiagnosed as having neuroleptic malignant syndrome
(NMS) which was later changed to serotonin syndrome due to a reaction between sertraline and
phenelzine. The authors suggest that monoamine oxidase inhibitor (MAOI) therapy should be
discontinued for at least two weeks before initiation of therapy with a selective serotonin reuptake
inhibitor (SSRI) and that before starting a MAOI, SSRI therapy should be discontinued for at least 5
half-lives of the parent drug and any active metabolites (Graber et al, 1994r).
d) Two cases reports suggested a possible interaction between fluoxetine and selegiline (Suchowersky
& de Vries, 1990r). One case involved a first episode of mania being observed approximately one
month after adding selegiline to fluoxetine therapy. The patient improved two months after both drugs
were discontinued, and no further details were provided. The second case involved diaphoresis,
vasoconstriction, and cyanosis of the hands which occurred in close temporal relationship to adding
fluoxetine and selegiline. Both drugs were discontinued, with relatively quick resolution of symptoms.
Rechallenge with fluoxetine alone occurred without incident.
3.5.1.CR Isoxicam
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.CS Ketoprofen
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 79
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
80 of 160
Page 80
of 244
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.CT Ketorolac
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.CU Lamifiban
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and antiplatelet agents has been associated
with an increased risk of bleeding. Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008;
Prod Info PROZAC(R) oral capsules, delayed-release capsules, solution, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an antiplatelet agent are given concurrently, monitor patient for
signs of increased bleeding (Prod Info PAXIL(R) oral tablets, suspension, 2008; Prod Info PROZAC(R) oral
capsules, delayed-release capsules, solution, 2008)
7) Probable Mechanism: unknown
3.5.1.CV Levomethadyl
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Any drug known to have the potential to prolong the QT interval should not be used with
levomethadyl. Possible pharmacodynamic interactions can occur between levomethadyl and potentially
arrhythmogenic agents such as fluvoxamine that prolong the QT interval (Prod Info Orlaam(R), 2001).
3) Severity: contraindicated
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Levomethadyl is contraindicated in patients being treated with fluvoxamine as it
may precipitate QT prolongation and interact with levomethadyl.
7) Probable Mechanism: unknown
3.5.1.CW Lexipafant
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and antiplatelet agents has been associated
with an increased risk of bleeding. Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008;
Prod Info PROZAC(R) oral capsules, delayed-release capsules, solution, 2008).
3) Severity: major
4) Onset: unspecified
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 80
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
81 of 160
Page 81
of 244
5) Substantiation: probable
6) Clinical Management: When an SSRI and an antiplatelet agent are given concurrently, monitor patient for
signs of increased bleeding (Prod Info PAXIL(R) oral tablets, suspension, 2008; Prod Info PROZAC(R) oral
capsules, delayed-release capsules, solution, 2008)
7) Probable Mechanism: unknown
3.5.1.CX Linezolid
1) Interaction Effect: CNS toxicity or serotonin syndrome (hypertension, hyperthermia, myoclonus, mental
status changes)
2) Summary: Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Concurrent
administration or overlapping therapy with fluvoxamine and a monoamine oxidase (MAO) inhibitor may
result in CNS toxicity or serotonin syndrome, a hyperserotonergic state characterized by symptoms such as
restlessness, myoclonus, changes in mental status, hyperreflexia, diaphoresis, shivering, and tremor. There
have been spontaneous reports of serotonin syndrome associated with concomitant use of linezolid and
serotonergic agents (Prod Info ZYVOX(R) IV injection, oral tablets, oral suspension, 2008; Prod Info Luvox
(R), 2000). If fluvoxamine and linezolid are used concomitantly, monitor closely for symptoms of serotonin
syndrome. Serotonin syndrome can be life-threatening. If serotonin syndrome develops, discontinue the
offending agents and provide supportive care and other therapy as necessary (Boyer & Shannon, 2005).
3) Severity: major
4) Onset: rapid
5) Substantiation: theoretical
6) Clinical Management: If fluoxamine and linezolid are used concomitantly, monitor closely for symptoms
of serotonin syndrome such as neuromuscular abnormalities (including hyper-reflexia, tremor, muscle
rigidity, clonus, peripheral hypertonicity, and shivering), autonomic hyperactivity (including tachycardia,
mydriasis, diaphoresis, the presence of bowel sounds, and diarrhea), and mental status changes (including
agitation and delirium). Serotonin syndrome can be life-threatening. If serotonin syndrome develops,
discontinue the offending agents and provide supportive care and other therapy as necessary (Boyer &
Shannon, 2005)
7) Probable Mechanism: inhibition of serotonin metabolism by monoamine oxidase
3.5.1.CY Lithium
1) Interaction Effect: possible increased lithium concentrations and/or an increased risk of SSRI-related
serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes)
2) Summary: Concomitant use of lithium and various SSRIs has been associated with enhanced side
effects of either or both drugs, and with or without elevated lithium levels. The combination has resulted in
neurotoxicity and increased lithium levels in one case report (Salama & Shafey, 1989a). Signs and
symptoms of lithium toxicity and serotonin syndrome have also been reported in patients who demonstrated
therapeutic serum lithium levels while on concurrent fluoxetine and lithium (Muly et al, 1993a; Noveske et al,
1989a). Two studies have failed to identify a pharmacokinetic interaction between lithium and citalopram
(Gram et al, 1993a; Baumann et al, 1996a). Combined administration of citalopram (40 mg daily for 10 days)
and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or
lithium. However, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose
in accordance with standard clinical practice. Lithium may enhance the serotonergic effects of citalopram,
therefore caution should be exercised when citalopram and lithium are coadministered (Prod Info Celexa(R),
2004). Concurrent use of fluvoxamine and lithium has led to case reports of increased lithium levels and
neurotoxicity, serotonin syndrome, somnolence, and mania (Salama & Shafey, 1989a; Ohman & Spigset,
1993a; Evans & Marwick, 1990; Burrai et al, 1991a). No pharmacokinetic interference was apparent during a
multiple-dose study of coadministered lithium and paroxetine (Prod Info Paxil CR(TM), 2003). If these two
agents are to be given concomitantly, the manufacturer suggests that caution be used until more clinical
experience is available. Drug interactions leading to lithium toxicity have been reported when lithium was
coadministered with fluoxetine and fluvoxamine (both in the same pharmacological class as paroxetine, eg,
selective serotonin reuptake inhibitors) (Ohman & Spigset, 1993a; Salama & Shafey, 1989a).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: established
6) Clinical Management: Monitor patients on concurrent lithium and selective serotonin reuptake inhibitor
therapy for increased plasma concentrations of lithium. In addition, monitor patients for signs and symptoms
associated with serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes).
7) Probable Mechanism: unknown
8) Literature Reports
a) Concomitant administration of oral lithium carbonate and oral fluoxetine resulted in increased lithium
serum levels with lithium toxicity in a 44-year-old woman with a bipolar affective disorder (Salama &
Shafey, 1989). Fluoxetine 20 mg daily was added to a regimen of lithium 1200 mg daily following patient
complaints of weakness, tiredness, decreased concentration, and early morning awakening. Lithium
serum levels increased to 1.7 mEq/L from a range of 0.75 to 1.15 mEq/L prior to fluoxetine. Fluoxetine
was discontinued and the dose of lithium decreased; this resulted in a decrease in the lithium serum
level within 48 hours to 1.2 mEq/L. The neurologic symptoms subsided within seven days as the lithium
serum level decreased to 0.9 mEq/L. The contribution of fluoxetine to lithium toxicity in this patient was
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 81
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
82 of 160
Page 82
of 244
obscured by the fact that the lithium was reduced at the time of fluoxetine withdrawal.
b) A 53-year old woman who had been taking fluoxetine 20 mg daily and lorazepam 0.5 mg four times
daily for a major depressive disorder had lithium 900 mg per day added to her regimen in order to
augment her response to fluoxetine. Within 48 hours, the patient became confused, ataxic, and
developed a coarse tremor in her right arm. Vital signs showed a rectal temperature of 101 degrees F,
and laboratory values were normal except for an elevated leukocyte count and slightly elevated bilirubin
level. After discontinuation of lithium and fluoxetine, the patient's symptoms resolved over the next four
days. At no point did the lithium levels reach a toxic level, suggesting that the patient's symptoms were
due to a toxic reaction between fluoxetine and lithium (Noveske et al, 1989).
c) Serotonin syndrome was precipitated when lithium 300 mg twice daily was added to a three-month
regimen of fluoxetine 40 mg per day. Five days later, the patient's lithium level was measured at 0.65
mEq/L and the dose was increased to 300 mg three times daily. Two days after this dosage change, the
patient experienced akathisia, myoclonus, hyperreflexia, shivering, tremor, diarrhea, and incoordination.
After discontinuation of lithium and initiation of cyproheptadine therapy, the patient's symptoms began to
improve. The patient was discharged on a regimen of fluoxetine 40 mg per day without further
symptoms of serotonin syndrome (Muly et al, 1993).
d) Eight healthy male volunteers completed three phases of an interaction study to determine the
effects of coadministered lithium and citalopram. All subjects were extensive metabolizers of sparteine,
indicating normal cytochrome P450 2D6 enzyme activity. Although lithium is not influenced by drug
oxidation, citalopram metabolites are excreted by the kidney, as is lithium. Each subject received
citalopram 40 mg alone as a single daily dose for 10 days, lithium 30 mmol (1980 mg) alone daily for
five days, and lithium coadministered with citalopram on days 3-7. At least two weeks separated each
treatment phase. Results showed that the concurrent administration of citalopram and lithium did not
significantly alter the pharmacokinetics of lithium (Gram et al, 1993).
e) Twenty-four patients experiencing depression (DSM III criteria) were randomized under double-blind
conditions to receive citalopram (40 mg to 60 mg daily) and lithium carbonate (800 mg daily) or placebo.
All of the subjects had failed to respond to four weeks of citalopram monotherapy. Lithium was
coadministered on days 29 to 42. No evidence of a pharmacokinetic interaction between lithium and
citalopram was noted, and cotherapy was well tolerated (Baumann et al, 1996).
f) Serotonin syndrome was described in a 53-year-old patient who was stabilized on lithium 1400 mg
daily (serum level 0.71 mmol/L) and was given fluvoxamine 50 mg daily. Over a 10-day period the
fluvoxamine dose was increased to 200 mg daily; tremor and difficulty with fine hand movements
developed. After two weeks, tremor, impaired motor function coordination, marked bilateral
hyperreflexia of biceps and knee jerks, and clonus in both ankles were seen. After 12 weeks of
continued therapy, during which time no further deterioration occurred, nortriptyline 100 mg daily
replaced fluvoxamine, and the neuromuscular symptoms abated over a 2-week period. After four weeks
the patient's neurological exam was normal (Ohman & Spigset, 1993).
g) Three cases of mania were reported in patients who were treated with lithium and fluvoxamine. The
mania appeared 10 days, four weeks, and five weeks, respectively, after cotherapy was begun.
Fluvoxamine was discontinued and, in two of the three patients, the mania resolved, and successful
treatment of depression occurred with lithium alone. The third patient improved, but depression
reappeared within a month of fluvoxamine discontinuation (Burrai et al, 1991).
h) In an open-labeled, placebo-controlled study, lithium 600 mg was administered to 16 subjects orally
twice daily on days one through eight and once in the morning on day nine. In addition, oral sertraline
100 mg or placebo was given twice, ten hours and two hours prior to lithium dosing on day nine. The
steady-state lithium level was only decreased by 1.4% (0.01 mEq/L) and the lithium renal clearance
increased by 6.9% (0.11 L/hour) when sertraline was coadministered. Seven subjects experienced side
effects, mainly tremors, after receiving lithium and sertraline, whereas no subjects who ingested
placebo and lithium experienced side effects (Wilner et al, 1991).
3.5.1.CZ Lornoxicam
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 82
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
83 of 160
Page 83
of 244
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.DA Maprotiline
1) Interaction Effect: maprotiline toxicity (dry mouth, urinary retention, sedation)
2) Summary: An interaction of fluvoxamine with tricyclic antidepressants (TCAs) was reported (Hartter et al,
1993g). Plasma concentrations of TCAs were increased when combined with fluvoxamine. This effect was
less prominent with maprotiline compared with imipramine, clomipramine, or amitriptyline. In addition, TCAs
appeared to increase fluvoxamine levels.
3) Severity: minor
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Monitor patients for excess tricyclic antidepressant side effects such as dry mouth
and lethargy. Maprotiline doses may need to be reduced in some clinical situations.
7) Probable Mechanism: decreased maprotiline metabolism
8) Literature Reports
a) Metabolism of tricyclic antidepressants coadministered with fluvoxamine was studied in eight
depressed patients (one patient received maprotiline) (Hartter et al, 1993f). Fluvoxamine was found to
interfere with N-demethylation of maprotiline. The combination of fluvoxamine and maprotiline led to
increased plasma levels of maprotiline and decreased concentrations of maprotiline's N-demethylated
metabolite, desmethylmaprotiline. Also, plasma levels of fluvoxamine were increased.
3.5.1.DB Mate
1) Interaction Effect: increased caffeine levels (insomnia, headache, restlessness, nervousness,
palpitations, and arrhythmias)
2) Summary: The primary pharmacologically-active ingredient of mate is caffeine. Fluvoxamine inhibits
CYP1A2 and CYP2D6 which are responsible for caffeine metabolism. Decreased caffeine clearance and
increased half-life have been demonstrated in humans (Jeppesen et al, 1996a). Signs and symptoms of
caffeine excess may result if the compounds are taken together. Patients should avoid mate use during
therapy with fluvoxamine in order to avoid possible complications.
3) Severity: moderate
4) Onset: rapid
5) Substantiation: theoretical
6) Clinical Management: Patients should be advised of the caffeine content of mate, and of symptoms of
excess if taken with fluvoxamine (insomnia, headache, restlessness, nervousness, palpitations, and
arrhythmias), as well as symptoms of caffeine withdrawal which may accompany abrupt discontinuation of
mate (e.g., headache, fatigue, depression, anxiety, and insomnia). Patients should avoid mate use during
therapy with fluvoxamine in order to avoid possible complications.
7) Probable Mechanism: inhibition of caffeine metabolism
8) Literature Reports
a) In an open, randomized, cross-over study of 8 volunteers, fluvoxamine significantly decreased
caffeine total clearance and increased caffeine half-life. Fluvoxamine was administered as 50 milligrams
(mg) for 4 days, then 100 mg for 8 days while subjects abstained from all caffeine intake. Caffeine 200
mg was then administered orally. Total clearance of caffeine decreased from 107 milliliters/minute
(mL/min) to 21 mL/min, and half-life increased from 5 hours to 31 hours. Patients taking fluvoxamine
should restrict caffeine intake (Jeppesen et al, 1996).
b) In vitro, fluvoxamine was found to be a very potent inhibitor of the formation of N-demethylated
caffeine metabolites with K1 values of 0.08 micromoles (mcmol) to 0.28 mcmol. The formation of 1,7dimethylxanthine was abolished by 10 mcmol of fluvoxamine, implying the N3-demethylation of caffeine
is almost entirely catalyzed by CYP1A2 (Rasmussen et al, 1998).
c) At least 14 metabolites are formed from caffeine whose main route of elimination is N3demethylation to paraxanthine (1,7-methylxanthine) which accounts for greater than 80% of caffeine
elimination (Lelo et al, 1986). CYP1A2 is the major enzyme metabolizing caffeine to 1,7dimethylxanthine (Berthou et al, 1991; Sesardic et al, 1990; Butler et al, 1989). CYP1A2 is also a major
enzyme in the formation of 3,7-dimethylxanthine and 1,3-dimethylxantihine from caffeine (Gu et al,
1992; Berthou et al, 1991; Grant et al, 1987).
3.5.1.DC Meclofenamate
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 83
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
84 of 160
Page 84
of 244
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.DD Mefenamic Acid
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.DE Melatonin
1) Interaction Effect: increased central nervous system depression
2) Summary: Fluvoxamine significantly increased melatonin levels and increased drowsiness when given
with melatonin in a study of 5 healthy volunteers (Hartter et al, 2000a). Endogenous melatonin levels
increased following fluvoxamine administration in 7 healthy subjects (Von Bahr et al, 2000). Fluvoxamine
may inhibit melatonin elimination (Hartter et al, 2000a), or metabolism via cytochrome P450 1A2 or 2C19
(Von Bahr et al, 2000). Patients taking fluvoxamine with or without melatonin supplementation should be
monitored for changes in sleep and central nervous system depression.
3) Severity: minor
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Monitor patients taking fluvoxamine with melatonin supplementation for changes in
sleep patterns and signs of excessive central nervous system depression. Downward titration of melatonin
dosages may be required during concomitant administration with fluvoxamine.
7) Probable Mechanism: inhibition of cytochrome P450 enzymes, possibly CYP1A2 and CYP2C19,
responsible for melatonin metabolism
8) Literature Reports
a) The bioavailability of oral melatonin was significantly increased after coadministration of
fluvoxamine. Five volunteers (one CYP2D6 poor metabolizer) were included in a study that was
designed to evaluate the effects of fluvoxamine on the pharmacokinetics of melatonin. A single dose of
melatonin 5 mg was administered to all subjects. One week later a single oral dose of fluvoxamine 50
mg was administered to all subjects. Blood samples were evaluated at certain time points after
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 84
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
85 of 160
Page 85
of 244
administration of each agent. An increase in melatonin serum concentrations occurred in all subjects
with a 23-fold increase in area under the concentration-time curve (AUC) (6.2 to 141.3 mcg h/L) and a
twelve-fold increase in maximum serum concentration (Cmax) (2.18 to 25.1 ng/ml) of melatonin. The
effects of fluvoxamine on melatonin pharmacokinetics were effectively greater in the poor CYP2D6
metabolizer. The author suggests that this is most likely due to inhibition of the elimination of melatonin
rather than an increased production of melatonin (Hartter et al, 2000).
3.5.1.DF Meloxicam
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.DG Methadone
1) Interaction Effect: increased plasma methadone levels
2) Summary: When fluvoxamine is added to patients receiving maintenance methadone therapy,
significantly increased methadone plasma level:dose ratios are seen. Symptoms of opioid toxicity were
observed in one patient. In another patient, opioid withdrawal symptoms were observed following
discontinuation of fluvoxamine (Prod Info Luvox(R), 1997w).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Monitor closely if adding or withdrawing fluvoxamine in patients on chronic
methadone.
7) Probable Mechanism: inhibition by fluvoxamine of cytochrome P450 3A4-mediated methadone
metabolism
8) Literature Reports
a) A 28-year-old female who was admitted to a hospital for the management of an acute exacerbation
of asthma had a stabilized medication regimen which included methadone 70 mg daily, diazepam 2 mg
twice daily, albuterol, ipratropium, ranitidine, and spironolactone. Three weeks before admission, she
had started fluvoxamine 100 mg daily. The patient's asthma was not considered to be in a significant
exacerbation upon further testing, although hypoxemia and hypercapnia indicating hypoventilation was
present. Methadone was decreased to 50 mg daily and diazepam was discontinued. Analysis of a blood
sample taken at admission showed that the serum methadone concentration was 262 ng/mL. Twelve
days later, oxygenation had improved and the methadone concentration was measured at 202 ng/mL.
The reduction in serum methadone concentration and clinical improvement observed after methadone
was decreased suggest that fluvoxamine may have inhibited the cytochrome P450 3A4-mediated
metabolism of methadone, although diazepam may have compounded this interaction (Alderman &
Frith, 1999).
3.5.1.DH Methylergonovine
1) Interaction Effect: an increased risk of ergotism (nausea, vomiting, vasospastic ischemia)
2) Summary: Because of the potential for serious toxicity including vasospasm that can occur with
increased plasma concentrations of ergot derivatives, the concurrent use of fluvoxamine and ergot
derivatives is contraindicated. Fluvoxamine and ergot derivatives are both metabolized by cytochrome P450
3A4 enzymes, and the competition for metabolism could result in an increased plasma concentration of the
ergot derivative (Prod Info Cafergot(R), 2002).
3) Severity: contraindicated
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 85
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
4)
5)
6)
7)
Filed 03/24/2010
Page
86 of 160
Page 86
of 244
Onset: rapid
Substantiation: probable
Clinical Management: The concurrent use of fluvoxamine and ergot derivatives is contraindicated.
Probable Mechanism: inhibition of cytochrome P450 3A4- mediated ergot metabolism by fluvoxamine
3.5.1.DI Methylphenidate
1) Interaction Effect: increased selective serotonin reuptake inhibitor plasma concentrations
2) Summary: Human pharmacologic studies have demonstrated that methylphenidate may inhibit the
metabolism of selective serotonin reuptake inhibitors (SSRIs). Downward dose adjustments of the SSRI may
be necessary when it is used concurrently with methylphenidate. Additionally, when initiating or
discontinuing methylphenidate, the SSRI dose may need to be adjusted as needed (Prod Info METADATE
CD(R) extended-release oral capsules, 2007).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Use caution when prescribing methylphenidate to patients who take an selective
serotonin reuptake inhibitor (SSRI). Concomitant use of methylphenidate and an SSRI may cause elevated
SSRI plasma concentrations. Consider a decrease in the dose of SSRI when these agents are
coadministered. Additionally, consider adjusting the SSRI dose if necessary when initiating or discontinuing
methylphenidate therapy (Prod Info METADATE CD(R) extended-release oral capsules, 2007).
7) Probable Mechanism: inhibition of selective serotonin reuptake inhibitor metabolism by methylphenidate
3.5.1.DJ Metoprolol
1) Interaction Effect: bradycardia and hypotension
2) Summary: Fluvoxamine may inhibit the metabolism of metoprolol, which resulted in bradycardia and/or
hypotension in one case (Prod Info Luvox(R), 1997o).
3) Severity: moderate
4) Onset: rapid
5) Substantiation: theoretical
6) Clinical Management: If metoprolol is coadministered with fluvoxamine, it is recommended that the initial
dose be reduced and that dose titration proceed more cautiously than usual. No dose change is required for
fluvoxamine. Monitor heart rate and blood pressure carefully.
7) Probable Mechanism: decreased metoprolol metabolism
3.5.1.DK Mexiletine
1) Interaction Effect: decreased mexiletine metabolism
2) Summary: In a single-dose study, concurrent administration of fluvoxamine and mexiletine reduced the
clearance of mexiletine by 37%, significantly increasing the mean serum peak concentration and area under
the concentration-time curve (Kusumoto et al, 2001a; Prod Info Mexitil(R), 2003).
3) Severity: moderate
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Monitor patients for signs and symptoms of mexiletine toxicity (nausea, dizziness,
cardiac arrhythmias). Monitor liver function, complete blood count, and electrocardiogram if mexiletine
toxicity is suspected, and reduce mexiletine dose as required.
7) Probable Mechanism: fluvoxamine-induced inhibition of CYP1A2-mediated mexiletine metabolism
8) Literature Reports
a) Co-administration of fluvoxamine with mexiletine significantly reduced the metabolism and clearance
of mexiletine. In a randomized, cross-over study, healthy Japanese men (n=6) received either a single
oral dose of mexiletine 200 milligrams (mg) or a 7-day regimen of oral fluvoxamine 50 mg twice daily
followed by fluvoxamine plus a single dose of mexiletine 200 mg on day 8. Serial blood samples were
measured over the 24 hours following each mexiletine dose. Thereafter, each subject crossed over to
the opposing study arm following a 7-day wash-out period. Compared with control values, concurrent
administration of fluvoxamine with mexiletine provoked a significant increase in the mean maximum
serum concentration (0.536 versus 0.623 micrograms/milliliter (mcg/mL), p=0.0074) and area under the
concentration-time curve (5.71 versus 7.46 mcg x hour/mL, p=0.0028). Co-administration significantly
decreased mean oral clearance by 37% (0.551 versus 0.341 L/hour/kilogram, p=0.015). The study
authors proposed fluvoxamine-induced inhibition of CYP1A2 metabolism as the mechanism of action
(Kusumoto et al, 2001).
3.5.1.DL Midazolam
1) Interaction Effect: elevated serum midazolam concentrations
2) Summary: Fluvoxamine coadministration (100 mg daily) with alprazolam 1 mg four times daily resulted in
a 2-fold increase in alprazolam steady-state plasma concentrations, AUC, Cmax, and half-life. Elevated
plasma levels of alprazolam were associated with impaired psychomotor performance and memory. This
suggests that fluvoxamine is a potent inhibitor of cytochrome P450 3A4 enzymes, which are responsible for
alprazolam metabolism. Because midazolam also relies on CYP3A4 for metabolism, a similar interaction
with fluvoxamine seems likely (Prod Info Luvox(R), 1997aa).
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 86
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
87 of 160
Page 87
of 244
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When midazolam and fluvoxamine are coadministered, monitor patients for
benzodiazepine toxicity (sedation, lethargy, slurred speech). Midazolam doses may need to be reduced, or
consider switching to a benzodiazepine eliminated by glucuronidation (eg, lorazepam, oxazepam,
temazepam).
7) Probable Mechanism: inhibition of midazolam metabolism due to cytochrome P450 3A4 enzyme
inhibition
3.5.1.DM Milnacipran
1) Interaction Effect: increased risk of serotonin syndrome (hypertension, hyperthermia, myoclonus, mental
status changes)
2) Summary: Concurrent use of milnacipran and an SSRI may result in hypertension, coronary artery
vasoconstriction or serotonin syndrome, which may be life-threatening. Symptoms of serotonin syndrome
may include restlessness, hallucinations, loss of coordination, fast heart beat, rapid changes in blood
pressure, increased body temperature, overreactive reflexes, nausea, vomiting, and diarrhea (Prod Info
SAVELLA(R) oral tablets, 2009).
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Coadministration of milnacipran and an SSRI may result in hypertension and
coronary artery vasoconstriction, through the additive serotonergic effects. If these agents are used
together, discuss the risks of serotonin syndrome with the patient and monitor closely for symptoms of
serotonin syndrome (restlessness, hyperthermia, hyperreflexia, incoordination), especially during treatment
initiation and dose increases (Prod Info SAVELLA(R) oral tablets, 2009).
7) Probable Mechanism: additive serotonergic effect
3.5.1.DN Mirtazapine
1) Interaction Effect: an increased risk of serotonin syndrome
2) Summary: Mirtazapine increases serotonin release and fluvoxamine inhibits the CYP450 1A2, 2C9, 2D6,
and 3A3/4-mediated mirtazapine metabolism. Concurrent use of fluvoxamine and mirtazapine resulted in
symptoms of serotonin syndrome in a 26-year-old female (Demers & Malone, 2001). If fluvoxamine and
mirtazapine are used together, monitor closely for symptoms of serotonin syndrome. Serotonin syndrome
can be life-threatening. If serotonin syndrome develops, discontinue the offending agents and provide
supportive care and other therapy as necessary (Boyer & Shannon, 2005).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: A case of serotonin syndrome was reported with concomitant use of fluvoxamine
and mirtazapine and therefore, concomitant use is discouraged(Demers & Malone, 2001). If fluvoxamine
and mirtazapine are used together, monitor closely for symptoms of serotonin syndrome such as
neuromuscular abnormalities (including hyper-reflexia, tremor, muscle rigidity, clonus, peripheral
hypertonicity, and shivering), autonomic hyperactivity (including tachycardia, mydriasis, diaphoresis, the
presence of bowel sounds, and diarrhea), and mental status changes (including agitation and delirium).
Serotonin syndrome can be life-threatening. If serotonin syndrome develops, discontinue the offending
agents and provide supportive care and other therapy as necessary (Boyer & Shannon, 2005).
7) Probable Mechanism: additive pharmacologic effects and inhibition of CYP1A2, 2C9, 2D6, and 3A3/4mediated metabolism of mirtazapine by fluvoxamine
8) Literature Reports
a) A 26-year-old woman with anorexia nervosa on fluvoxamine for a total of 4 months developed
symptoms of serotonin syndrome after mirtazapine was added. She was on fluvoxamine 150 mg/day for
2 months with a subsequent increase to 200 mg/day for 2 months before starting mirtazapine. The
symptoms of twitching, tremors, agitation, restlessness, and "feeling like she could crawl out of her skin"
developed over a period of 4 days after starting mirtazapine 30 mg/day. Symptoms rapidly progressed
to twitching, tremors, and restlessness. She was hospitalized with further symptoms of diaphoresis,
flushing, fasciculations, and nausea and treated with cyproheptadine 4 mg every 6 hours,
acetaminophen, and intravenous fluids. She remained afebrile throughout the event. Symptoms
completely resolved within 24 hours. She was discharged on 50 mg/day of fluvoxamine and no
recurrence the following day. The interaction was attributed to multiple mechanisms. Mirtazapine
increases the release of serotonin via the 5-hydroxytryptamine (serotonin) (5-HT) 1 receptors but it is
also a 5-HT2 and 5-HT3 receptors blocker. Fluvoxamine decreases mirtazapine metabolism by
inhibiting cytochrome P-450 1A2, 2C9, 2D6, and 3A3/4 enzymes, and may have increased the
mirtazapine serum levels resulting in increased mirtazapine adverse effects (Demers & Malone, 2001).
b) A letter to the editor (Isbister et al, 2001) disagreed with the case report that fluvoxamine and
mirtazapine resulted in serotonin syndrome (Demers & Malone, 2001). Their argument is that the
diagnostic criteria used was unreliable; mirtazapine, a 5-hydroxytryptamine 2A receptor blocker, is
unlikely to cause serotonin syndrome and may actually offer benefit in treating it; and the symptoms
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 87
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
88 of 160
Page 88
of 244
were adverse effects related to increased concentrations of mirtazapine from inhibition of metabolism by
fluvoxamine (Isbister et al, 2001).
3.5.1.DO Moclobemide
1) Interaction Effect: CNS toxicity or serotonin syndrome (hypertension, hyperthermia, myoclonus, mental
status changes)
2) Summary: Concurrent administration or overlapping therapy with fluvoxamine and a monoamine oxidase
(MAO) inhibitor may result in CNS toxicity or serotonin syndrome, a hyperserotonergic state characterized
by symptoms such as restlessness, myoclonus, changes in mental status, hyperreflexia, diaphoresis,
shivering, and tremor. Serious, even fatal, reactions have been reported with concomitant use of serotonin
specific reuptake inhibitors and MAO inhibitors (Prod Info Luvox(R), 1997e; Neuvonen et al, 1993a).
Although not reported specifically with moclobemide in therapeutic doses, a similar reaction may occur.
Concomitant use is not recommended.
3) Severity: major
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: In general, concurrent use of a serotonin specific reuptake inhibitor and a MAO
inhibitor should be avoided. Wait at least 14 days after discontinuing a MAO inhibitor before initiating therapy
with fluvoxamine. Wait at least 14 days after discontinuing fluvoxamine before initiating therapy with a MAO
inhibitor.
7) Probable Mechanism: inhibition of serotonin metabolism by monoamine oxidase
8) Literature Reports
a) Concomitant use of selective serotonin reuptake inhibitors and monoamine oxidase inhibitors can
produce a toxic reaction known as serotonin syndrome (Sternbach, 1991a). Serotonin syndrome is a
condition of serotonergic hyperstimulation and manifests as restlessness, myoclonus, changes in
mental status, hyperreflexia, diaphoresis, shivering, and tremor. If the syndrome is not recognized and
correctly treated, death can result.
b) A study reported five fatal overdose cases due to serotonin syndrome. In three of the five cases, the
drug combination that induced the fatal syndrome was moclobemide, a selective monoamine oxidase
inhibitor, and citalopram. Of the three patients, blood concentrations of moclobemide ranged from five
times the therapeutic level to 50 times the therapeutic level, and citalopram concentrations ranged from
normal therapeutic levels to five times the therapeutic level (Neuvonen et al, 1993).
3.5.1.DP Morniflumate
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.DQ Nabumetone
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 88
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
89 of 160
Page 89
of 244
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.DR Nadroparin
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 89
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
90 of 160
Page 90
of 244
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.DS Naproxen
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.DT Naratriptan
1) Interaction Effect: an increased risk of serotonin syndrome
2) Summary: Rare incidences of weakness, hyperreflexia, and incoordination have been reported with the
concurrent use of a selective serotonin reuptake inhibitor (SSRI) and a 5-hydroxytryptamine-1 (5HT-1)
agonist (Prod Info Amerge(TM), 2002). Concurrent use of a triptan and an SSRI may result in serotonin
syndrome which may be life-threatening. Symptoms of serotonin syndrome may include restlessness,
hallucinations, loss of coordination, fast heart beat, rapid changes in blood pressure, increased body
temperature, overreactive reflexes, nausea, vomiting, and diarrhea. Clinicians should be aware that triptans
may be commonly used intermittently and that either the triptan or the SSRI may be prescribed by a different
physician. Discuss the risks of serotonin syndrome with patients who are prescribed this combination and
monitor them closely for symptoms of serotonin syndrome (US Food and Drug Administration, 2006).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Coadministration of a triptan, such as naratriptan, and an SSRI may result in a lifethreatening condition called serotonin syndrome. Be aware that triptans may be commonly used
intermittently and that either the triptan or the SSRI may be prescribed by a different physician. If these
agents are used together, discuss the risks of serotonin syndrome with the patient and monitor closely for
symptoms of serotonin syndrome (restlessness, hyperthermia, hyperreflexia, incoordination).
7) Probable Mechanism: additive pharmacologic effects resulting in excessive serotonergic stimulation
3.5.1.DU Nialamide
1) Interaction Effect: CNS toxicity or serotonin syndrome (hypertension, hyperthermia, myoclonus, mental
status changes)
2) Summary: Concurrent administration or overlapping therapy with fluvoxamine and a monoamine oxidase
(MAO) inhibitor may result in CNS toxicity or serotonin syndrome, a hyperserotonergic state characterized
by symptoms such as restlessness, myoclonus, changes in mental status, hyperreflexia, diaphoresis,
shivering, and tremor. Serious, even fatal, reactions have been reported with concomitant use of selective
serotonin reuptake inhibitors and MAO inhibitors (Prod Info Luvox(R), 1997y; Lappin & Auchincloss, 1994q;
Graber et al, 1994q; Suchowersky & de Vries, 1990q). Concomitant use is not recommended.
3) Severity: major
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Concurrent use of fluvoxamine and a MAO inhibitor should be avoided. Wait at
least two weeks after discontinuing an MAO inhibitor before initiating therapy with fluvoxamine. Wait at least
two weeks after discontinuing fluvoxamine before initiating therapy with a MAO inhibitor.
7) Probable Mechanism: serotonin reuptake inhibition
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 90
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
91 of 160
Page 91
of 244
8) Literature Reports
a) Concomitant use of serotonin specific reuptake inhibitors and monoamine oxidase inhibitors can
produce a toxic reaction known as serotonin syndrome (Sternbach, 1991l). Serotonin syndrome is a
condition of serotonergic hyperstimulation and manifests as restlessness, myoclonus, changes in
mental status, hyperreflexia, diaphoresis, shivering, and tremor. If the syndrome is not recognized and
correctly treated, death can result.
b) A 26-year old woman who had been taking isocarboxazid for eight weeks stopped taking the drug
for 11 days before beginning therapy with sertraline. After a single 100 mg sertraline dose, the patient
became restless and developed leg twitches. The patients was later admitted to the emergency room
with diaphoresis, tachycardia, hyperreflexia, and various neuromuscular disturbances. After treatment
with diazepam and propranolol the patient did not improve. The patient was then given two 4 mg doses
of cyproheptadine an hour apart, with notable improvement in symptoms after the second dose (Lappin
& Auchincloss, 1994p).
c) A drug interaction occurred in a 61-year old woman whose regimen of sertraline 100 mg twice daily
was added to a regimen of lithium, phenelzine, thioridazine, and doxepin. Three hours after taking the
first sertraline dose, the patient was found in a semicomatose state, with elevated body temperature,
increased pulse, increased respiration rate, and a blood pressure of 140/110 mm Hg. After
transportation to the hospital, the patient was misdiagnosed as having neuroleptic malignant syndrome
(NMS) which was later changed to serotonin syndrome due to a reaction between sertraline and
phenelzine. The authors suggest that monoamine oxidase inhibitor (MAOI) therapy should be
discontinued for at least two weeks before initiation of therapy with a selective serotonin reuptake
inhibitor (SSRI) and that before starting a MAOI, SSRI therapy should be discontinued for at least five
half-lives of the parent drug and any active metabolites (Graber et al, 1994p).
d) Two cases reports suggested a possible interaction between fluoxetine and selegiline (Suchowersky
& de Vries, 1990p). One case involved a first episode of mania being observed approximately one
month after adding selegiline to fluoxetine therapy. The patient improved two months after both drugs
were discontinued, and no further details were provided. The second case involved diaphoresis,
vasoconstriction, and cyanosis of the hands which occurred in close temporal relationship to adding
fluoxetine and selegiline. Both drugs were discontinued, with relatively quick resolution of symptoms.
Rechallenge with fluoxetine alone occurred without incident.
3.5.1.DV Niflumic Acid
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.DW Nimesulide
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 91
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
92 of 160
Page 92
of 244
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.DX Olanzapine
1) Interaction Effect: an increased risk of olanzapine adverse effects
2) Summary: Fluvoxamine inhibits cytochrome P450 1A2 enzymes and may inhibit olanzapine elimination
(Prod Info Zyprexa(R), 1999). The clinical significance of this interaction is unknown since olanzapine is
metabolized by multiple enzyme systems.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Monitor patients for excessive olanzapine adverse effects (orthostatic hypotension,
tachycardia, transaminase elevations, seizures).
7) Probable Mechanism: inhibition of olanzapine elimination
8) Literature Reports
a) A patient experienced elevated olanzapine plasma levels during coadministration of fluvoxamine.
The patient was taking fluvoxamine and olanzapine for several months for schizophrenia and secondary
depression. She appeared to move rigidly, had a slight tremor of both hands and mydriasis. Olanzapine
concentration was 120 mcg/L and fluvoxamine concentration was 70 mcg/L. Olanzapine was decreased
in increments from 15 mg/day to 5 mg/day. Fourteen days after the last decrease in dose, olanzapine
plasma levels were 38 mcg/L. Tremor and rigidity disappeared, however, mydriasis persisted.
Fluvoxamine was replaced by paroxetine which resulted in paroxetine concentration of 0.027 mg/L and
olanzapine concentration of 22 mcg/L (de Jong et al, 2001).
b) Addition of fluvoxamine to olanzapine therapy may result in olanzapine-induced side effects or
intoxication. Eight chronic schizophrenic patients were being treated for not less than 3 months with 1020 mg/day of olanzapine. The dose of olanzapine was unchanged for not less than 8 weeks prior to the
study and remained stable throughout the study period. Fluvoxamine 100 mg/day was added to
olanzapine treatment at the start of the study (week 0) and continued for 8 weeks. Olanzapine
concentrations increased during fluvoxamine treatment 1.58-fold from week 0 to week 1, 1.42-fold from
week 0 to week 4, and 1.81-fold from week 0 to week 8. Percentage change from week 0 to week 8
ranged from 12% to 112%. Mean concentrations of the N-demethylated metabolite were not
significantly changed. Even though all eight patients had higher olanzapine blood serum concentrations
on week 8 than on week 1, the ratio of increase of olanzapine blood serum concentrations from week 0
to week 8 did not correlate significantly with fluvoxamine serum levels (p greater than 0.05). This study
confirmed that the addition of fluvoxamine to a stable dose of olanzapine increased olanzapine
concentrations in the blood serum. Combined olanzapine and fluvoxamine should be used cautiously
and controlled clinically and by therapeutic drug monitoring to avoid olanzapine-induced side effects or
intoxication (Hiemke et al, 2002).
3.5.1.DY Oxaprozin
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 92
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
93 of 160
Page 93
of 244
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.DZ Oxycodone
1) Interaction Effect: an increased risk of serotonin syndrome (tachycardia, hyperthermia, myoclonus,
mental status changes)
2) Summary: Coadministration of oxycodone and fluvoxamine has resulted in the development of serotonin
syndrome in a 70-year-old woman. Presenting symptoms included confusion, nausea, fever, clonus,
hyperreflexia, and tachycardia. Caution is advised if fluvoxamine and oxycodone are coadministered.
Monitor patients for signs and symptoms of serotonin syndrome (tachycardia, hyperthermia, myoclonus,
mental status changes) (Karunatilake & Buckley, 2006).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Concomitant administration of fluvoxamine and oxycodone may increase the risk
of developing serotonin syndrome. If these agents are coadministered, monitor patients for symptoms of
serotonin syndrome (tachycardia, hyperthermia, myoclonus, mental status changes).
7) Probable Mechanism: additive pharmacologic effects resulting in excessive serotonergic stimulation
8) Literature Reports
a) Concurrent administration of oxycodone and fluvoxamine resulted in a serotonin syndrome in a 70year-old woman. The patient was receiving fluvoxamine 200 mg and doxepin 50 mg for several months
for treatment of depression. Subsequent to a fall, the patients was started on slow-release oral
oxycodone 40 mg twice daily, and 2 days later, short-acting oral oxycodone 10 mg, to be used on an
"as needed" basis, was added to her regimen. After a dose of about 60 mg oxycodone taken over 24
hours, the patient presented to the emergency department in a state of confusion, with symptoms
including nausea, fever, clonus, hyperreflexia, and shivering. The patient also had mydriasis, transient
atrial fibrillation, tachycardia, and an elevated creatinine kinase level. Fluvoxamine, doxepin, and
oxycodone were discontinued and the patient was treated with 5 doses of oral acetaminophen 1,000 mg
over the next 2 days. The patient's neurologic and cardiovascular symptoms improved steadily over the
next 48 hours. Prior to discharge, doxepin therapy was re-initiated with no apparent adverse effects.
However, patient was not rechallenged with either fluvoxamine or oxycodone while she was in the
hospital. According to the Naranjo probability scale, the interaction falls into the probable category
(Karunatilake & Buckley, 2006).
3.5.1.EA Parecoxib
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.EB Pargyline
1) Interaction Effect: CNS toxicity or serotonin syndrome (hypertension, hyperthermia, myoclonus, mental
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 93
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
94 of 160
Page 94
of 244
status changes)
2) Summary: Concurrent administration or overlapping therapy with fluvoxamine and a monoamine oxidase
(MAO) inhibitor may result in CNS toxicity or serotonin syndrome, a hyperserotonergic state characterized
by symptoms such as restlessness, myoclonus, changes in mental status, hyperreflexia, diaphoresis,
shivering, and tremor. Serious, even fatal, reactions have been reported with concomitant use of selective
serotonin reuptake inhibitors and MAO inhibitors (Prod Info Luvox(R), 1997l; Lappin & Auchincloss, 1994g;
Graber et al, 1994g; Suchowersky & de Vries, 1990g). Concomitant use is not recommended.
3) Severity: major
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Concurrent use of fluvoxamine and a MAO inhibitor should be avoided. Wait at
least two weeks after discontinuing an MAO inhibitor before initiating therapy with fluvoxamine. Wait at least
two weeks after discontinuing fluvoxamine before initiating therapy with a MAO inhibitor.
7) Probable Mechanism: serotonin reuptake inhibition
8) Literature Reports
a) Concomitant use of serotonin specific reuptake inhibitors and monoamine oxidase inhibitors can
produce a toxic reaction known as serotonin syndrome (Sternbach, 1991e). Serotonin syndrome is a
condition of serotonergic hyperstimulation and manifests as restlessness, myoclonus, changes in
mental status, hyperreflexia, diaphoresis, shivering, and tremor. If the syndrome is not recognized and
correctly treated, death can result.
b) A 26-year old woman who had been taking isocarboxazid for eight weeks stopped taking the drug
for 11 days before beginning therapy with sertraline. After a single 100 mg sertraline dose, the patient
became restless and developed leg twitches. The patients was later admitted to the emergency room
with diaphoresis, tachycardia, hyperreflexia, and various neuromuscular disturbances. After treatment
with diazepam and propranolol the patient did not improve. The patient was then given two 4 mg doses
of cyproheptadine an hour apart, with notable improvement in symptoms after the second dose (Lappin
& Auchincloss, 1994f).
c) A drug interaction occurred in a 61-year old woman whose regimen of sertraline 100 mg twice daily
was added to a regimen of lithium, phenelzine, thioridazine, and doxepin. Three hours after taking the
first sertraline dose, the patient was found in a semicomatose state, with elevated body temperature,
increased pulse, increased respiration rate, and a blood pressure of 140/110 mm Hg. After
transportation to the hospital, the patient was misdiagnosed as having neuroleptic malignant syndrome
(NMS) which was later changed to serotonin syndrome due to a reaction between sertraline and
phenelzine. The authors suggest that monoamine oxidase inhibitor (MAOI) therapy should be
discontinued for at least two weeks before initiation of therapy with a selective serotonin reuptake
inhibitor (SSRI) and that before starting a MAOI, SSRI therapy should be discontinued for at least five
half-lives of the parent drug and any active metabolites (Graber et al, 1994f).
d) Two cases reports suggested a possible interaction between fluoxetine and selegiline (Suchowersky
& de Vries, 1990f). One case involved a first episode of mania being observed approximately one
month after adding selegiline to fluoxetine therapy. The patient improved two months after both drugs
were discontinued, and no further details were provided. The second case involved diaphoresis,
vasoconstriction, and cyanosis of the hands which occurred in close temporal relationship to adding
fluoxetine and selegiline. Both drugs were discontinued, with relatively quick resolution of symptoms.
Rechallenge with fluoxetine alone occurred without incident.
3.5.1.EC Parnaparin
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 94
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
95 of 160
Page 95
of 244
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.ED Pentosan Polysulfate Sodium
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 95
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
96 of 160
Page 96
of 244
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.EE Phenelzine
1) Interaction Effect: CNS toxicity or serotonin syndrome (hypertension, hyperthermia, myoclonus, mental
status changes)
2) Summary: Concurrent administration or overlapping therapy with fluvoxamine and a monoamine oxidase
(MAO) inhibitor may result in CNS toxicity or serotonin syndrome, a hyperserotonergic state characterized
by symptoms such as restlessness, myoclonus, changes in mental status, hyperreflexia, diaphoresis,
shivering, and tremor. Serious, even fatal, reactions have been reported with concomitant use of serotonin
specific reuptake inhibitors and MAO inhibitors (Prod Info Luvox(R), 1997m; Lappin & Auchincloss, 1994i;
Graber et al, 1994i; Suchowersky & de Vries, 1990i). Concomitant use of phenelzine and fluvoxamine is
contraindicated (Prod Info Nardil(R), 1997).
3) Severity: contraindicated
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Concurrent use of fluvoxamine and phenelzine is contraindicated . Wait at least
two weeks after discontinuing an MAO inhibitor before initiating therapy with fluvoxamine. Wait at least two
weeks after discontinuing fluvoxamine before initiating therapy with a MAO inhibitor.
7) Probable Mechanism: serotonin reuptake inhibition
8) Literature Reports
a) Concomitant use of serotonin specific reuptake inhibitors and monoamine oxidase inhibitors can
produce a toxic reaction known as serotonin syndrome (Sternbach, 1991f). Serotonin syndrome is a
condition of serotonergic hyperstimulation and manifests as restlessness, myoclonus, changes in
mental status, hyperreflexia, diaphoresis, shivering, and tremor. If the syndrome is not recognized and
correctly treated, death can result.
b) A 26-year old woman who had been taking isocarboxazid for eight weeks stopped taking the drug
for 11 days before beginning therapy with sertraline. After a single 100 mg sertraline dose, the patient
became restless and developed leg twitches. The patients was later admitted to the emergency room
with diaphoresis, tachycardia, hyperreflexia, and various neuromuscular disturbances. After treatment
with diazepam and propranolol the patient did not improve. The patient was then given two 4 mg doses
of cyproheptadine an hour apart, with notable improvement in symptoms after the second dose (Lappin
& Auchincloss, 1994h).
c) A drug interaction was reported in a 61-year old woman in which sertraline 100 mg twice daily was
added to a regimen of lithium, phenelzine, thioridazine, and doxepin. Three hours after taking the first
sertraline dose, the patient was found in a semicomatose state, with elevated body temperature,
increased pulse, increased respiration rate, and a blood pressure of 140/110 mm Hg. After
transportation to the hospital, the patient was misdiagnosed as having neuroleptic malignant syndrome
(NMS) which was later changed to serotonin syndrome due to a reaction between sertraline and
phenelzine. The authors suggest that monoamine oxidase inhibitor (MAOI) therapy should be
discontinued for at least two weeks before initiation of therapy with a selective serotonin reuptake
inhibitor (SSRI) and that before starting a MAOI, SSRI therapy should be discontinued for at least 5
half-lives of the parent drug and any active metabolites (Graber et al, 1994h).
d) Two cases reports suggested a possible interaction between fluoxetine and selegiline (Suchowersky
& de Vries, 1990h). One case involved a first episode of mania being observed approximately one
month after adding selegiline to fluoxetine therapy. The patient improved two months after both drugs
were discontinued, and no further details were provided. The second case involved diaphoresis,
vasoconstriction, and cyanosis of the hands which occurred in close temporal relationship to adding
fluoxetine and selegiline. Both drugs were discontinued, with relatively quick resolution of symptoms.
Rechallenge with fluoxetine alone occurred without incident.
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 96
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
97 of 160
Page 97
of 244
3.5.1.EF Phenindione
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.EG Phenprocoumon
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 97
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
98 of 160
Page 98
of 244
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.EH Phenylbutazone
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 98
7/1/2009
MICROMEDEX®
Healthcare Series Document
: Document 78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Page
99 of 160
Page 99
of 244
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.EI Phenytoin
1) Interaction Effect: an increased risk of phenytoin toxicity (ataxia, hyperreflexia, nystagmus, tremors)
2) Summary: Fluvoxamine inhibits several of the isoenzymes of the cytochrome P450 enzyme system
(oxidative metabolism); IA2, IIC9, and IIIA4. Since phenytoin is eliminated at least partially via the CYP450
IIC9 pathway, it is possible that coadministration with fluvoxamine may cause elevations in phenytoin
plasma levels (Prod Info Luvox(R), 1997).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Consideration should be given to monitoring of phenytoin serum levels when
fluvoxamine is added or withdrawn from therapy and dosage adjustments made accordingly. Patients should
be counseled to be aware of the potential side effects of phenytoin toxicity such as drowsiness, ataxia, and
nystagmus, and to notify their physician if such side effects occur.
7) Probable Mechanism: decreased oxidative metabolism
8) Literature Reports
a) During an in vitro study, the inhibitory effects of fluvoxamine on cytochrome P450 2C9 were
evaluated using p-hydroxylation of phenytoin as an established index reaction reflecting CYP2C9
activity. In vivo, p-hydroxylation of phenytoin depends on the formation of 5-(p-hydroxy-phenyl)-5phenylhydantoin (HPPH). Fluvoxamine, a strong inhibitor of HPPH, impaired the formation of HPPH,
which can lead to an increase in steady-state phenytoin levels (Schmider et al, 1997).
b) Phenytoin intoxication occurred in a patient after administration of fluvoxamine. Serum phenytoin
concentration dramatically increased from 16.6 to 49.1 mcg/mL during treatment with fluvoxamine.
Fluvoxamine may inhibit the metabolism of PHT, mediated by cytochrome P450 2C9 (CYP2C9) and
CYP 2C19 enzymes (Mamiya et al, 2000).
3.5.1.EJ Pirazolac
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.EK Piroxicam
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 99
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof100
of 160
Page 100
244
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.EL Pirprofen
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.EM Procarbazine
1) Interaction Effect: CNS toxicity or serotonin syndrome (hypertension, hyperthermia, myoclonus, mental
status changes)
2) Summary: Concurrent administration or overlapping therapy with fluvoxamine and a monoamine oxidase
(MAO) inhibitor may result in CNS toxicity or serotonin syndrome, a hyperserotonergic state characterized
by symptoms such as restlessness, myoclonus, changes in mental status, hyperreflexia, diaphoresis,
shivering, and tremor. Serious, even fatal, reactions have been reported with concomitant use of selective
serotonin reuptake inhibitors and MAO inhibitors (Prod Info Luvox(R), 1997p; Lappin & Auchincloss, 1994m;
Graber et al, 1994m; Suchowersky & de Vries, 1990m). Concomitant use is not recommended.
3) Severity: major
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Concurrent use of fluvoxamine and a MAO inhibitor should be avoided. Wait at
least two weeks after discontinuing an MAO inhibitor before initiating therapy with fluvoxamine. Wait at least
two weeks after discontinuing fluvoxamine before initiating therapy with a MAO inhibitor.
7) Probable Mechanism: serotonin reuptake inhibition
8) Literature Reports
a) Concomitant use of serotonin specific reuptake inhibitors and monoamine oxidase inhibitors can
produce a toxic reaction known as serotonin syndrome (Sternbach, 1991i). Serotonin syndrome is a
condition of serotonergic hyperstimulation and manifests as restlessness, myoclonus, changes in
mental status, hyperreflexia, diaphoresis, shivering, and tremor. If the syndrome is not recognized and
correctly treated, death can result.
b) A 26-year old woman who had been taking isocarboxazid for eight weeks stopped taking the drug
for 11 days before beginning therapy with sertraline. After a single 100 mg sertraline dose, the patient
became restless and developed leg twitches. The patients was later admitted to the emergency room
with diaphoresis, tachycardia, hyperreflexia, and various neuromuscular disturbances. After treatment
with diazepam and propranolol the patient did not improve. The patient was then given two 4 mg doses
of cyproheptadine an hour apart, with notable improvement in symptoms after the second dose (Lappin
& Auchincloss, 1994l).
c) A drug interaction was reported in a 61-year old woman in which sertraline 100 mg twice daily was
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 100
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof101
of 160
Page 101
244
added to a regimen of lithium, phenelzine, thioridazine, and doxepin. Three hours after taking the first
sertraline dose, the patient was found in a semicomatose state, with elevated body temperature,
increased pulse, increased respiration rate, and a blood pressure of 140/110 mm Hg. After
transportation to the hospital, the patient was misdiagnosed as having neuroleptic malignant syndrome
(NMS) which was later changed to serotonin syndrome due to a reaction between sertraline and
phenelzine. The authors suggest that monoamine oxidase inhibitor (MAOI) therapy should be
discontinued for at least two weeks before initiation of therapy with a selective serotonin reuptake
inhibitor (SSRI) and that before starting a MAOI, SSRI therapy should be discontinued for at least five
half-lives of the parent drug and any active metabolites (Graber et al, 1994l).
d) Two cases reports suggested a possible interaction between fluoxetine and selegiline (Suchowersky
& de Vries, 1990l). One case involved a first episode of mania being observed approximately one month
after adding selegiline to fluoxetine therapy. The patient improved two months after both drugs were
discontinued, and no further details were provided. The second case involved diaphoresis,
vasoconstriction, and cyanosis of the hands which occurred in close temporal relationship to adding
fluoxetine and selegiline. Both drugs were discontinued, with relatively quick resolution of symptoms.
Rechallenge with fluoxetine alone occurred without incident.
3.5.1.EN Propranolol
1) Interaction Effect: bradycardia and hypotension
2) Summary: Propranolol serum concentrations may increase significantly during concomitant therapy with
fluvoxamine. Elevated propranolol serum concentrations may be associated with an increased risk of
bradycardia and hypotension (Prod Info Luvox(R), 1997c).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Carefully monitor heart rate and blood pressure. The propranolol does may need
to be reduced if bradycardia or hypotension develop. Alternatively, use of atenolol, a beta-blocker which
does not undergo hepatic metabolism and is not affected by fluvoxamine, may be considered.
7) Probable Mechanism: reduced beta blocker metabolism
8) Literature Reports
a) Coadministration of propranolol (160 mg per day) and fluvoxamine (100 mg per day) in healthy
volunteers resulted in a mean 5-fold increase in minimum propranolol serum concentrations. This was
associated with a slight reduction in heart rate and blood pressure (Prod Info Luvox(R), 1997b; van
Harten, 1993).
3.5.1.EO Propyphenazone
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.EP Proquazone
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 101
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof102
of 160
Page 102
244
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.EQ Ramelteon
1) Interaction Effect: increased ramelteon plasma concentrations with increased risk of side effects
2) Summary: Concurrent administration of fluvoxamine and ramelteon is contraindicated due to significantly
increased ramelteon plasma concentrations with concurrent fluvoxamine use (Prod Info ROZEREM(R) oral
tablets, 2008).
3) Severity: contraindicated
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Concurrent administration of fluvoxamine and ramelteon is contraindicated (Prod
Info ROZEREM(R) oral tablets, 2008).
7) Probable Mechanism: inhibition of CYP1A2-mediated ramelteon metabolism by fluvoxamine
8) Literature Reports
a) Fluvoxamine, a strong CYP1A2 inhibitor, significantly increases ramelteon plasma concentrations
when used concurrently. When a single dose of ramelteon 16 mg was coadministered to subjects who
received fluvoxamine 100 mg twice daily for 3 days prior, the ramelteon AUC and Cmax increased
approximately 190-fold and 70-fold, respectively (Prod Info ROZEREM(R) oral tablets, 2008).
3.5.1.ER Rasagiline
1) Interaction Effect: CNS toxicity or serotonin syndrome (hypertension, hyperthermia, myoclonus, mental
status changes)
2) Summary: Concurrent administration or overlapping therapy with selective serotonin reuptake inhibitors,
including fluvoxamine, and non-selective MAOIs or the selective MAO-B inhibitor selegiline, has been
reported to cause serious, sometimes fatal reactions. Signs and symptoms included hyperthermia, rigidity,
myoclonus, autonomic instability with rapid vital sign fluctuations, and mental status changes progressing to
extreme agitation, delirium, and coma. Similar reactions have been reported with serotonin-norepinephrine
reuptake inhibitors (SNRIs) and non-selective MAOIs or selegiline. Rasagiline clinical trials did not allow
concomitant use of fluvoxamine; the combination of rasagiline and fluvoxamine should be avoided. Wait at
least two weeks after discontinuing rasagiline before initiating therapy with fluvoxamine (Prod Info AZILECT
(R) oral tablets, 2006).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: Concurrent use of fluvoxamine and rasagiline should be avoided. Wait at least two
weeks after discontinuing rasagiline before initiating therapy with fluvoxamine.
7) Probable Mechanism: inhibition of serotonin metabolism by monoamine oxidase
8) Literature Reports
a) Concomitant use of serotonin specific reuptake inhibitors and monoamine oxidase inhibitors can
produce a toxic reaction known as serotonin syndrome (Sternbach, 1991g). Serotonin syndrome is a
condition of serotonergic hyperstimulation and manifests as restlessness, myoclonus, changes in
mental status, hyperreflexia, diaphoresis, shivering, and tremor. If the syndrome is not recognized and
correctly treated, death can result.
3.5.1.ES Reviparin
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 102
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof103
of 160
Page 103
244
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.ET Rizatriptan
1) Interaction Effect: an increased risk of serotonin syndrome
2) Summary: There have been case reports of weakness, hyperreflexia, and incoordination following
concomitant use of sumatriptan, a 5-hydroxytryptamine-1 (5HT-1) agonist, and a serotonin specific reuptake
inhibitor (SSRI) (Prod Info Imitrex(R), 1998). Because rizatriptan is a 5HT 1B/1D receptor agonist, a similar
interaction between SSRIs and rizatriptan may occur (Prod Info Maxalt(R), 1998a). Concurrent use of a
triptan and an SSRI may result in serotonin syndrome which may be life-threatening. Symptoms of serotonin
syndrome may include restlessness, hallucinations, loss of coordination, fast heart beat, rapid changes in
blood pressure, increased body temperature, overreactive reflexes, nausea, vomiting, and diarrhea.
Clinicians should be aware that triptans may be commonly used intermittently and that either the triptan or
the SSRI may be prescribed by a different physician. Discuss the risks of serotonin syndrome with patients
who are prescribed this combination and monitor them closely for symptoms of serotonin syndrome (US
Food and Drug Administration, 2006).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Coadministration of a triptan, such as rizatriptan, and an SSRI may result in a lifethreatening condition called serotonin syndrome. Be aware that triptans may be commonly used
intermittently and that either the triptan or the SSRI may be prescribed by a different physician. If these
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 103
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof104
of 160
Page 104
244
agents are used together, discuss the risks of serotonin syndrome with the patient and monitor closely for
symptoms of serotonin syndrome (restlessness, hyperthermia, hyperreflexia, incoordination).
7) Probable Mechanism: additive pharmacologic effects resulting in excessive serotonergic stimulation
8) Literature Reports
a) Twelve healthy volunteers received paroxetine 20 mg daily for two weeks and a single dose of
rizatriptan 10 mg. Plasma concentrations of rizatriptan were not altered by the administration of
paroxetine (Prod Info Maxalt(R), 1998).
3.5.1.EU Rofecoxib
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.EV Ropivacaine
1) Interaction Effect: increased plasma levels of ropivacaine
2) Summary: Ropivacaine is metabolized in the liver by the cytochrome P450 1A2 (CYP1A2) enzyme
system to 3-hydroxyropivacaine, the major metabolite. Drugs which inhibit CYP1A2, such as fluvoxamine,
can potentially interact with the metabolism of ropivacaine. This would result in decreased renal clearance
and increased plasma concentrations of ropivacaine (Jokinen et al, 2000a; Prod Info Naropin(TM), 1996).
3) Severity: moderate
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Care must be taken to monitor the patient for signs of local anesthetic toxicity with
the coadministration of ropivacaine and fluvoxamine.
7) Probable Mechanism: inhibition by fluvoxamine of cytochrome P450 1A2-mediated ropivacaine
metabolism
8) Literature Reports
a) In a randomized, three-way crossover study, 12 healthy volunteers received a single dose of
ropivacaine 40 mg as an intravenous infusion alone or combined with either oral fluvoxamine 25 mg or
ketoconazole 100 mg twice daily for two days. The combined therapy with ropivacaine and
ketoconazole demonstrated no clinically significant differences in the pharmacokinetic measurements
obtained. The authors theorized that cytochrome P450 3A4 (CYP3A4) inhibition, as measured by
ketoconazole, has little effect on the pharmacokinetics of ropivacaine. However, CYP1A2 inhibition, as
measured by fluvoxamine, may result in a clinically relevant drug interaction with repeated
administration. In the presence of fluvoxamine, ropivacaine total plasma clearance decreased by 68%
(from 354 mL/min to 112 mL/min). The observed reduction in the total plasma clearance after
fluvoxamine arises from a decrease in 3-hydroxyropivacaine formation, which is likely mediated by
CYP1A2. Additionally, the half-life of ropivacaine increased from 1.9 hours to 3.6 hours when given with
fluvoxamine. The reduction in ropivacaine clearance during fluvoxamine administration is likely to be of
minor relevance when ropivacaine is given as a single dose. However, repeated administration of
ropivacaine in a patient also receiving fluvoxamine may result in toxic ropivacaine plasma
concentrations (Arlander et al, 1998).
b) Inhibition of cytochrome P450 1A2 (CYP1A2) by fluvoxamine considerably reduced elimination of
ropivacaine. The eight patients in this randomized, double-blind, cross-over, four phase study ingested
erythromycin 1500 mg daily for 6 days, fluvoxamine 100 mg for 5 days, both erythromycin and
fluvoxamine, or placebo. Each subject received ropivacaine 0.6 mg/kg IV over 30 minutes as a single
dose. Fluvoxamine increased both the AUC (p less than 0.001) of ropivacaine 3.7-fold, prolonged the
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 104
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof105
of 160
Page 105
244
half-life from 2.3 to 7.4 h (p less than 0.01), and decreased clearance 77% (p less than 0.001) when
compared with placebo. Fluvoxamine increased the AUC of 2,6-pipecoloxylidide (PPX), a ropivacaine
metabolite, 2.5-fold (p less than 0.001) and the Cmax of PPX 2.8-fold (p less than 0.001) and
decreased the plasma levels of 3-OH-ropivacaine to below the limit of quantitation. Erythromycin had
minor effects on the pharmacokinetics of ropivacaine. The combination of fluvoxamine and
erythromycin, however, when compared with fluvoxamine alone, further increased the AUC of
ropivacaine by 50% (p less than 0.01), and prolonged the half-life from 7.4 to 11.9 h (p less than 0.01).
The author concludes that fluvoxamine-induced cytochrome P450 1A2 inhibition considerably reduces
elimination of ropivacaine. Coadministration of fluvoxamine and erythromycin increases plasma
ropivacaine levels further by decreasing its clearance (Jokinen et al, 2000).
3.5.1.EW Selegiline
1) Interaction Effect: CNS toxicity or serotonin syndrome (hypertension, hyperthermia, myoclonus, mental
status changes)
2) Summary: Concurrent administration or overlapping therapy with fluvoxamine and a monoamine oxidase
(MAO) inhibitor may result in CNS toxicity or serotonin syndrome, a hyperserotonergic state characterized
by symptoms such as restlessness, myoclonus, changes in mental status, hyperreflexia, diaphoresis,
shivering, and tremor. Serious, even fatal, reactions have been reported with concomitant use of serotonin
specific reuptake inhibitors and MAO inhibitors (Prod Info Luvox(R), 1997v; Lappin & Auchincloss, 1994o;
Graber et al, 1994o; Suchowersky & de Vries, 1990o). Concomitant use is not recommended.
3) Severity: major
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Concurrent use of fluvoxamine and a MAO inhibitor should be avoided. Wait at
least two weeks after discontinuing an MAO inhibitor before initiating therapy with fluvoxamine. Wait at least
two weeks after discontinuing fluvoxamine before initiating therapy with a MAO inhibitor.
7) Probable Mechanism: serotonin reuptake inhibition
8) Literature Reports
a) Concomitant use of serotonin specific reuptake inhibitors and monoamine oxidase inhibitors can
produce a toxic reaction known as serotonin syndrome (Sternbach, 1991g). Serotonin syndrome is a
condition of serotonergic hyperstimulation and manifests as restlessness, myoclonus, changes in
mental status, hyperreflexia, diaphoresis, shivering, and tremor. If the syndrome is not recognized and
correctly treated, death can result.
b) A 26-year old woman who had been taking isocarboxazid for eight weeks stopped taking the drug
for 11 days before beginning therapy with sertraline. After a single 100 mg sertraline dose, the patient
became restless and developed leg twitches. The patients was later admitted to the emergency room
with diaphoresis, tachycardia, hyperreflexia, and various neuromuscular disturbances. After treatment
with diazepam and propranolol the patient did not improve. The patient was then given two 4 mg doses
of cyproheptadine an hour apart, with notable improvement in symptoms after the second dose (Lappin
& Auchincloss, 1994n).
c) A drug interaction occurred in a 61-year old woman whose regimen of sertraline 100 mg twice daily
was added to a regimen of lithium, phenelzine, thioridazine, and doxepin. Three hours after taking the
first sertraline dose, the patient was found in a semicomatose state, with elevated body temperature,
increased pulse, increased respiration rate, and a blood pressure of 140/110 mm Hg. After
transportation to the hospital, the patient was misdiagnosed as having neuroleptic malignant syndrome
(NMS) which was later changed to serotonin syndrome due to a reaction between sertraline and
phenelzine. The authors suggest that monoamine oxidase inhibitor (MAOI) therapy should be
discontinued for at least two weeks before initiation of therapy with a selective serotonin reuptake
inhibitor (SSRI) and that before starting a MAOI, SSRI therapy should be discontinued for at least 5
half-lives of the parent drug and any active metabolites (Graber et al, 1994n).
d) Two cases reports suggested a possible interaction between fluoxetine and selegiline (Suchowersky
& de Vries, 1990n). One case involved a first episode of mania being observed approximately one
month after adding selegiline to fluoxetine therapy. The patient improved two months after both drugs
were discontinued, and no further details were provided. The second case involved diaphoresis,
vasoconstriction, and cyanosis of the hands which occurred in close temporal relationship to adding
fluoxetine and selegiline. Both drugs were discontinued, with relatively quick resolution of symptoms.
Rechallenge with fluoxetine alone occurred without incident.
3.5.1.EX Sibrafiban
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and antiplatelet agents has been associated
with an increased risk of bleeding. Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008;
Prod Info PROZAC(R) oral capsules, delayed-release capsules, solution, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 105
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof106
of 160
Page 106
244
6) Clinical Management: When an SSRI and an antiplatelet agent are given concurrently, monitor patient for
signs of increased bleeding (Prod Info PAXIL(R) oral tablets, suspension, 2008; Prod Info PROZAC(R) oral
capsules, delayed-release capsules, solution, 2008)
7) Probable Mechanism: unknown
3.5.1.EY Sibutramine
1) Interaction Effect: an increased risk of serotonin syndrome (hypertension, hyperthermia, myoclonus,
mental status changes)
2) Summary: Sibutramine inhibits the reuptake of norepinephrine, dopamine, and serotonin. In addition, the
two major metabolites of sibutramine, M1 and M2, also inhibit the reuptake of these neurotransmitters. A
hyperserotonergic state, termed serotonin syndrome, may result if sibutramine is given concurrently with a
selective serotonin reuptake inhibitor. Coadministration of sibutramine and selective serotonin reuptake
inhibitors is not recommended (Prod Info Meridia(R), 1997).
3) Severity: major
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Sibutramine should not be administered with serotonergic agents, including
selective serotonin reuptake inhibitors, because of the increased risk of serotonin syndrome.
7) Probable Mechanism: additive pharmacologic effects resulting in excessive serotonergic stimulation
8) Literature Reports
a) Serotonin syndrome is a condition of serotonergic hyperstimulation and manifests as restlessness,
myoclonus, changes in mental status, hyperreflexia, diaphoresis, shivering, and tremor. If the syndrome
is not recognized and correctly treated, death can result (Sternbach, 1991b).
3.5.1.EZ St John's Wort
1) Interaction Effect: an increased risk of serotonin syndrome (hypertension, hyperthermia, myoclonus,
mental status changes)
2) Summary: Case reports describe the onset of serotonin syndrome-like symptoms, mania, and hypomania
following the addition of St. John's Wort to sertraline, fluoxetine, and paroxetine therapy (Spinella & Eaton,
2002c; Barbanel et al, 2000a; Waksman et al, 2000a; Lantz et al, 1999a). A patient exhibited a syndrome
resembling sedative/hypnotic intoxication after adding St. John's Wort to paroxetine therapy (Gordon,
1998a). St. John's Wort is thought to inhibit serotonin reuptake and may have mild monoamine oxidase
inhibitory activity (Singer et al, 1999; Thiede & Walper, 1994), which when added to selective serotonin
reuptake inhibitors may result in serotonin syndrome.
3) Severity: major
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Patients should be advised to wait two weeks after stopping St. John's Wort before
restarting selective serotonin reuptake inhibitor therapy. If a patient plans to replace selective serotonin
reuptake inhibitor (SSRI) therapy with St. John's Wort, the half-life of the specific SSRI should be taken into
consideration, waiting at least 5 half-lives for the SSRI to be metabolized out of the body.
7) Probable Mechanism: additive serotonergic effect
8) Literature Reports
a) Five cases have been reported of serotonin syndrome in the elderly after combining prescription
antidepressants and St. John's Wort. Case 1 developed dizziness, nausea, vomiting and a headache 4
days after starting St. John's Wort 300 milligrams (mg) three times daily combined with sertraline 50 mg
daily. Her symptoms resolved 2 to 3 days after stopping all medications. Case 2 developed nausea,
epigastric pain and anxiety 3 days after starting St. John's Wort 300 mg twice daily combined with
sertraline 75 mg daily. His symptoms resolved in one week after discontinuing both medications, and he
resumed sertraline use without complications. The third case developed nausea, vomiting, anxiety, and
confusion 2 days after starting St. John's Wort 300 mg twice daily combined with sertraline 50 mg daily.
His symptoms improved in 4 to 5 days after stopping both medications and taking cyproheptadine 4 mg
three times daily. Case 4 developed nausea, anxiety, restless, and irritability 2 days after starting St.
John's Wort 300 mg three times daily combined with sertraline 50 mg daily. Cyproheptadine 4 mg twice
daily was administered for seven days, and his symptoms improved in 1 week after stopping the
medication. Cases 1 through 4 resumed their prescriptive sertraline after symptoms subsided and had
no further problems. Case 5 developed nausea, vomiting and restlessness 3 days after starting St.
John's Wort 300 mg three times daily combined with nefazodone 100 mg twice daily. She continued to
take St. John's Wort but discontinued the nefazodone and over 1 week her symptoms Improved. She
refused to resume therapy with nefazodone, but continued therapy with St. John's Wort and mild to
moderate symptoms of depression and anxiety returned (Lantz et al, 1999).
b) A 50-year-old female taking St. John's Wort 600 mg daily experienced symptoms of sedative
intoxication when she ingested a single dose of paroxetine 20 mg. She was incoherent, groggy, slowmoving, and complained of nausea and weakness. Prior to starting St. John's Wort, she had been
receiving paroxetine 40 mg daily for eight months without adverse effects. After a night of sleep, she
returned to her baseline mental status (Gordon, 1998).
c) A 61-year-old female experienced restlessness and involuntary movements of her extremities after
beginning paroxetine 20 milligrams (mg) two days after discontinuing St. John's Wort 600 mg daily. The
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 106
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof107
of 160
Page 107
244
patient reported agitation and akathisia 8 hours after taking the first dose of paroxetine. She presented
with diaphoresis and involuntary movement of all extremities with hyperreflexia and rigidity. Blood
pressure, heart rate, and temperature were normal. After admission, blood pressure increased to
200/116 mmHg and heart rate increased to 145 beats per minute. Creatine kinase increased from 212
units/liter (U/L) initially to 1024 U/L. The patient was managed with supportive care and lorazepam and
discharged after two days (Waksman et al, 2000).
d) A 28-year-old male developed a manic syndrome following comedication with St. John's Wort and
sertraline. The patient was also on testosterone replacement therapy following bilateral orchidectomy 2
years earlier, but testosterone levels were subtherapeutic. The patient was prescribed sertraline 50
milligrams daily for depression following a 2 week trial of St. John's Wort per patient preference (dose
not specified). Before sertraline was started, the patient was instructed to discontinue St. John'sWort,
but continued it despite this advice. The patient experienced improved mood so did not see his
physician, believing that he did not need further treatment. Over 2 months, the patient had elated mood,
was irritable, and overspent, buying a car he could not afford, and was ultimately arrested for stealing
fuel for the car. On arrest, he was referred to psychiatric services due to irritability and disinhibition. He
was observed to be over-aroused, distractible, have flight of ideas, and grandiose delusions, leading to
a diagnosis of a manic episode. The authors state the possibility of the manic state resulting from
sertraline therapy alone, and that St. John's Wort may have increased the risk as a result of monoamine
oxidase inhibition. Since the patient's testosterone level was subnormal, the possibility of its contribution
to the manic state was considered low. However, the patient had elevated gonadotropin levels
(luteinizing hormone and follicle-stimulating hormone) which may have predisposed the patient to mania
(Barbanel et al, 2000).
e) A 42-year-old female experienced symptoms consistent with a mixed hypomanic episode following
concomitant use of fluoxetine, buspirone, Ginkgo biloba, and St. John's Wort. The symptoms resolved
following discontinuation of Ginkgo and St. John's Wort. The patient was being treated for depression
following a mild traumatic brain injury with fluoxetine 20 milligrams (mg) twice daily and buspirone 15
mg twice daily. Several weeks prior to presentation, buspirone was increased to 20 mg twice daily for
persistent anxiety and the patient began taking Ginkgo biloba, melatonin, and St. John's Wort in
unspecified doses. Melatonin was considered unlikely to have contributed to her symptoms. Ginkgo and
St. John's Wort were considered possible contributors since they may potentiate antidepressants, and
considering the temporal relationship between the use of the herbs and onset of symptoms and
discontinuation of the herbs and resolution of symptoms. However, the brain injury was considered a
possible contributor (Spinella & Eaton, 2002b).
3.5.1.FA Sulfinpyrazone
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and antiplatelet agents has been associated
with an increased risk of bleeding. Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008;
Prod Info PROZAC(R) oral capsules, delayed-release capsules, solution, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an antiplatelet agent are given concurrently, monitor patient for
signs of increased bleeding (Prod Info PAXIL(R) oral tablets, suspension, 2008; Prod Info PROZAC(R) oral
capsules, delayed-release capsules, solution, 2008)
7) Probable Mechanism: unknown
3.5.1.FB Sulindac
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 107
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof108
of 160
Page 108
244
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.FC Sulodexide
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and antiplatelet agents has been associated
with an increased risk of bleeding. Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008;
Prod Info PROZAC(R) oral capsules, delayed-release capsules, solution, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an antiplatelet agent are given concurrently, monitor patient for
signs of increased bleeding (Prod Info PAXIL(R) oral tablets, suspension, 2008; Prod Info PROZAC(R) oral
capsules, delayed-release capsules, solution, 2008)
7) Probable Mechanism: unknown
3.5.1.FD Sumatriptan
1) Interaction Effect: an increased risk of serotonin syndrome
2) Summary: There have been case reports of weakness, hyperreflexia, and incoordination following
concomitant use of a triptan, such as sumatriptan, and a serotonin specific reuptake inhibitor (SSRI), such
as fluvoxamine (Prod Info Imitrex(R), 2002). Concurrent use of a triptan and an SSRI may result in serotonin
syndrome which may be life-threatening. Symptoms of serotonin syndrome may include restlessness,
hallucinations, loss of coordination, fast heart beat, rapid changes in blood pressure, increased body
temperature, overreactive reflexes, nausea, vomiting, and diarrhea. Clinicians should be aware that triptans
may be commonly used intermittently and that either the triptan or the SSRI may be prescribed by a different
physician. Discuss the risks of serotonin syndrome with patients who are prescribed this combination and
monitor them closely for symptoms of serotonin syndrome (US Food and Drug Administration, 2006).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Coadministration of a triptan, such as sumatriptan, and an SSRI, such as
fluvoxamine, may result in a life-threatening condition called serotonin syndrome. Be aware that triptans may
be commonly used intermittently and that either the triptan or the SSRI may be prescribed by a different
physician. If these agents are used together, discuss the risks of serotonin syndrome with the patient and
monitor closely for symptoms of serotonin syndrome (restlessness, hyperthermia, hyperreflexia,
incoordination).
7) Probable Mechanism: additive pharmacologic effects resulting in excessive serotonergic stimulation
3.5.1.FE Suprofen
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 108
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof109
of 160
Page 109
244
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.FF Tacrine
1) Interaction Effect: an increase in the plasma concentration of tacrine
2) Summary: Two studies involving healthy volunteers and single doses of tacrine found that fluvoxamine
inhibited the metabolism of tacrine, causing an increase in the area under the concentration-time curve
(AUC) of tacrine and three of its metabolites. Fluvoxamine inhibits cytochrome P450 1A2 enzymes, and
these same enzymes are responsible for tacrine metabolism. Whether this interaction would be present in
Alzheimer's patients receiving multiple tacrine doses is not known (Becquemont et al, 1997a; Teilmann
Larsen et al, 1999a).
3) Severity: moderate
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: While the exact clinical implication of this drug interaction is uncertain, monitor
patients receiving tacrine and fluvoxamine concurrently for excessive tacrine adverse effects, including
cholinergic effects. Also monitor liver function for increased hepatotoxicity.
7) Probable Mechanism: inhibition of cytochrome P450 1A2 enzymes by fluvoxamine
8) Literature Reports
a) A randomized, double-blind, two-period cross-over study involving 14 healthy male volunteers
investigated the influence of fluvoxamine on the pharmacokinetics of a single-dose of tacrine. Study
subjects received either fluvoxamine 100 mg or placebo once daily for six days, and a single dose of
tacrine 40 mg was coadministered on day 6. The tacrine area under the concentration-time curve (AUC)
increased from 27 ng/hr/mL to 224 ng/hr/mL in the presence of fluvoxamine. Maximum concentration
(Cmax) of tacrine also increased from 7 ng/mL to 39 ng/mL during the fluvoxamine period. No
significant changes in the time to reach Cmax (tmax) and the half-life of tacrine were observed. The
AUC values of three tacrine metabolites were also significantly increased, but to a lesser extent than the
AUC of tacrine. Whether these same results are seen in Alzheimer's patients receiving multiple doses of
tacrine is not known (Becquemont et al, 1997).
b) Eighteen healthy male volunteers participated in an open, randomized crossover study to establish
whether fluvoxamine in clinically relevant doses was able to inhibit the formation of tacrine metabolites.
Volunteers received tacrine 40 mg as a single dose and fluvoxamine 50 mg or 100 mg once daily for
five days, followed by a dose of tacrine 20 mg. Fluvoxamine reduced the apparent oral clearance of
tacrine by 85%. Specifically, fluvoxamine reduced the formation of 1- and 2-hydroxytacrine, but the
formation of 4-hydroxytacrine was not affected. Whether the inhibition of these metabolites reduced
tacrine-induced hepatotoxicity requires further investigation (Teilmann Larsen et al, 1999).
3.5.1.FG Tapentadol
1) Interaction Effect: increased risk of serotonin syndrome (hypertension, hyperthermia, myoclonus, mental
status changes)
2) Summary: Concurrent use of tapentadol and a selective serotonin reuptake inhibitor (SSRI) may result in
serotonin syndrome, which may be life-threatening. Symptoms of serotonin syndrome may include
restlessness, hallucinations, loss of coordination, fast heart beat, rapid changes in blood pressure, increased
body temperature, overreactive reflexes, nausea, vomiting, and diarrhea (Prod Info tapentadol immediate
release oral tablets, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Coadministration of tapentadol and an SSRI may result in a life-threatening
condition called serotonin syndrome. If these agents are used together, monitor the patient closely for
symptoms of serotonin syndrome (restlessness, hyperthermia, hyperreflexia, incoordination), especially
during treatment initiation and dose increases (Prod Info tapentadol immediate release oral tablets, 2008).
7) Probable Mechanism: additive serotonergic effect
3.5.1.FH Tenidap
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 109
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof110
of 160
Page 110
244
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.FI Tenoxicam
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.FJ Terfenadine
1) Interaction Effect: cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Fluvoxamine should not be used in combination with terfenadine. Although there is no direct
experience with this combination, fluvoxamine appears to be a potent inhibitor of the cytochrome P450IIIA4
isozyme, the enzyme primarily responsible for the metabolism of terfenadine. Inhibition of this enzyme may
result in elevated terfenadine concentrations; increased plasma concentrations of terfenadine are associated
with QT prolongation and torsades de pointes, which can be fatal (Prod Info Luvox(R), 1997h).
3) Severity: contraindicated
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Concurrent use of fluvoxamine and terfenadine is contraindicated.
7) Probable Mechanism: inhibition by fluvoxamine of terfenadine metabolism
3.5.1.FK Theophylline
1) Interaction Effect: theophylline toxicity (nausea, vomiting, palpitations, seizures)
2) Summary: Fluvoxamine-theophylline combination therapy has produced toxic serum concentrations of
theophylline (Sperber, 1991a; van den Brekel & Harrington, 1994; Perucca et al, 1994; Lorenz et al, 1996a).
The reported mechanism of action is fluvoxamine's inhibitory effect on the hepatic cytochrome P4501A2
(CYP1A2), the microsome responsible for catalyzing theophylline metabolism (Prod Info Luvox(R), 1997r).
3) Severity: major
4) Onset: delayed
5) Substantiation: established
6) Clinical Management: Careful monitoring of theophylline serum concentration is required. Theophylline
doses should be reduced to one-third of the usual daily maintenance dose if fluvoxamine is coadministered.
No dose adjustment is necessary for fluvoxamine.
7) Probable Mechanism: decreased theophylline metabolism
8) Literature Reports
a) Fluvoxamine appeared to be responsible for substantially increased serum theophylline levels and
symptoms of theophylline toxicity in an 11-year-old boy taking sustained-release theophylline 300 mg
twice daily (Sperber, 1991). Both drugs were discontinued, and theophylline was later reinstated (dose
not specified) with no further evidence of toxicity.
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 110
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof111
of 160
Page 111
244
b) An increase in theophylline plasma concentrations from 13 mg/L to 40 mg/L was found after
fluvoxamine was added to therapy. The patient was an 83-year-old man who was receiving sustained
release theophylline 600 mg per day (Diot et al, 1991).
c) Fluvoxamine 50 mg twice a day given concurrently with theophylline 1000 mg daily resulted in a
theophylline plasma concentration of 32 mcg/mL and nausea and tachycardia in a 75-year-old male
with normal liver function (Lorenz et al, 1996). Theophylline clearance was calculated to be 43 mL/h
before the addition of fluvoxamine and 22 mL/h after four doses.
d) In 12 healthy nonsmoking volunteers with steady-state fluvoxamine levels, the pharmacokinetics of a
single dose of theophylline 375 mg were evaluated. Theophylline clearance decreased three-fold.
Therefore, it is recommended that the daily maintenance dose of theophylline be reduced by two-thirds
in a patient also receiving fluvoxamine (Prod Info Luvox(R), 1997q).
3.5.1.FL Thioridazine
1) Interaction Effect: an increased risk of thioridazine toxicity, cardiotoxicity (QT prolongation, torsades de
pointes, cardiac arrest)
2) Summary: Fluvoxamine inhibits the metabolism of thioridazine, possibly through the inhibition of
cytochrome P450 2D6 (CYP2D6) resulting in toxicity. The resulting elevated levels of thioridazine would be
expected to enhance the prolongation of the QT interval associated with thioridazine and may increase the
risk of serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes-type arrhythmias (Prod Info
Mellaril(R), 2000a).
3) Severity: contraindicated
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Due to the potential for significant, possibly life-threatening, proarrhythmic effects,
concurrent administration of thioridazine and fluvoxamine is contraindicated.
7) Probable Mechanism: inhibition of cytochrome P450 2D6-mediated thioridazine metabolism
8) Literature Reports
a) The serum concentrations of thioridazine and its two metabolites, mesoridazine and sulforidazine,
were evaluated in ten male schizophrenic patients aged 36 to 78 years at three separate time points. All
patients were receiving thioridazine monotherapy for the management of schizophrenia at a mean dose
of 88 mg daily. Fluvoxamine 50 mg daily was coadministered for one week. Plasma levels of
thioridazine and its metabolites were measured during monotherapy with thioridazine, after one week of
concurrent therapy with thioridazine and fluvoxamine, and two weeks after fluvoxamine was
discontinued. Following one week of combination therapy with fluvoxamine and thioridazine,
thioridazine levels increased 225%, mesoridazine levels increased 219%, and sulforidazine
concentrations rose 258%. Even two weeks after the discontinuation of fluvoxamine, three patients
continued to show elevated thioridazine and metabolite levels. No clinical symptoms were attributed to
the interaction between these two agents (Carrillo et al, 1999).
b) The metabolism of thioridazine is inhibited by drugs such as fluvoxamine due to reduced cytochrome
P450 2D6 and 1A2 isozyme activity. The elevated levels of thioridazine would be expected to enhance
the prolongation of the QT interval associated with thioridazine. This, in turn, may increase the risk of
serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes-type arrhythmias (Prod Info
Mellaril(R), 2000).
3.5.1.FM Tiaprofenic Acid
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 111
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof112
of 160
Page 112
244
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.FN Ticlopidine
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and antiplatelet agents has been associated
with an increased risk of bleeding. Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008;
Prod Info PROZAC(R) oral capsules, delayed-release capsules, solution, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an antiplatelet agent are given concurrently, monitor patient for
signs of increased bleeding (Prod Info PAXIL(R) oral tablets, suspension, 2008; Prod Info PROZAC(R) oral
capsules, delayed-release capsules, solution, 2008)
7) Probable Mechanism: unknown
3.5.1.FO Tinzaparin
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 112
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof113
of 160
Page 113
244
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.FP Tirofiban
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and antiplatelet agents has been associated
with an increased risk of bleeding. Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008;
Prod Info PROZAC(R) oral capsules, delayed-release capsules, solution, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an antiplatelet agent are given concurrently, monitor patient for
signs of increased bleeding (Prod Info PAXIL(R) oral tablets, suspension, 2008; Prod Info PROZAC(R) oral
capsules, delayed-release capsules, solution, 2008)
7) Probable Mechanism: unknown
3.5.1.FQ Tizanidine
1) Interaction Effect: increased tizanidine plasma concentrations
2) Summary: Concomitant use of fluvoxamine and tizanidine is contraindicated. Use of these drugs together
has resulted in increased plasma concentrations and half-life of tizanidine (Prod Info tizanidine hcl tablets,
2006).(Prod Info Zanaflex (R) Tablets, 2004). Concurrent administration of fluvoxamine, a potent CYP1A2
inhibitor, and tizanidine induced a profound increase in tizanidine bioavailability. The inhibition of CYP1A2mediated tizanidine metabolism provokes clinically significant hypotension and alteration of consciousness
(Granfors et al, 2004). In a retrospective case series, tizanidine-associated adverse events occurred
significantly more often in patients treated concomitantly with fluvoxamine and tizanidine compared with
tizanidine monotherapy (Momo et al, 2004).
3) Severity: contraindicated
4) Onset: rapid
5) Substantiation: established
6) Clinical Management: The concomitant use of fluvoxamine and tizanidine is contraindicated. Use of
tizanidine with fluvoxamine can increase the plasma concentrations of tizanidine (Prod Info tizanidine hcl
tablets, 2006) which may lead to decreased blood pressure, psychomotor impairment, and excessive
drowsiness (Granfors et al, 2004).
7) Probable Mechanism: inhibition of CYP1A2-mediated tizanidine metabolism by fluvoxamine
8) Literature Reports
a) In a study of 10 healthy volunteers treated with fluvoxamine and tizanidine, the half-life, Cmax, and
AUC of tizanidine increased by 12-fold, 33-fold, and 3-fold, respectively (Prod Info tizanidine hcl tablets,
2006).
b) Coadministration of fluvoxamine with tizanidine resulted in profound increases in tizanidine
bioavailability due to P450 CYP1A2-mediated inhibition of tizanidine metabolism and was associated
with multiple adverse clinical effects. In a randomized, double-blind, crossover study (4-week wash out
period), healthy subjects (n=10) received a 4-day regimen of fluvoxamine 100 milligrams (mg) or
placebo once daily. On day 4, each subject received a single oral dose of tizanidine 4 mg. Serial blood
pharmacokinetic analysis was performed over the next 24 hours, in conjunction with measurement of
pharmacodynamic response. When compared with placebo, the presence of fluvoxamine dramatically
increased tizanidine mean maximum serum concentration (by 1210% (from 2.2 to 26.6
nanograms/milliliter), p=0.000001), mean area under the concentration-time curve (AUC 0-infinity; by
3260%, p=0.000002), and mean elimination half-life from 1.5 hours to 4.3 hours (by 290%, p=0.00004).
Pharmacodynamic responses to fluvoxamine-enhanced tizanidine exposure were also dramatic: mean
systolic blood pressure declined by 35 millimeters mercury (mmHg; from 115 to 79 mmHg), mean
diastolic blood pressure decreased by 20 mmHg (from 66 to 46 mmHg), heart rate decreased by 4
beats per minute, and subjectively perceived drowsiness (0-100 visual analogue scale) increased by a
mean of 42 points compared with the placebo-tizanidine phase (p=0.000009, p=0.00002, p=0.007, and
p=0.0002, respectively). During the fluvoxamine-tizanidine phase, all subjects experienced somnolence
and dizziness for between 3 and 6 hours after the dose of tizanidine. There was no compensatory
tachycardic response to the treatment-associated hypotension (Granfors et al, 2004).
c) In a retrospective case series review of patients treated with tizanidine (n=913), tizanidine-related
adverse events occurred with significantly greater frequency in patients treated concurrently with
fluvoxamine and tizanidine (n=23) when compared with tizanidine monotherapy (26.1% (6/23) versus
5.3%, respectively; p less than 0.0001). Bradycardia occurred in the 6 affected patients, with dizziness,
hypothermia, drowsiness, hypotension, and impaired speech occurring in order of descending
frequency (Momo et al, 2004).
3.5.1.FR Tolmetin
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 113
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof114
of 160
Page 114
244
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.FS Toloxatone
1) Interaction Effect: CNS toxicity or serotonin syndrome (hypertension, hyperthermia, myoclonus, mental
status changes)
2) Summary: Concurrent administration or overlapping therapy with fluvoxamine and a monoamine oxidase
(MAO) inhibitor may result in CNS toxicity or serotonin syndrome, a hyperserotonergic state characterized
by symptoms such as restlessness, myoclonus, changes in mental status, hyperreflexia, diaphoresis,
shivering, and tremor. Serious, even fatal, reactions have been reported with concomitant use of selective
serotonin reuptake inhibitors and MAO inhibitors (Prod Info Luvox(R), 1997n; Lappin & Auchincloss, 1994k;
Graber et al, 1994k; Suchowersky & de Vries, 1990k). As a reversible and selective monoamine oxidase
inhibitor, toloxatone may not potentiate the effects of selective serotonin reuptake inhibitors to the same
frequency, extent, and duration observed with other MAOIs. However, until further studies confirm the safety
and efficacy of this combined therapy, caution should be used.
3) Severity: major
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Concurrent use of fluvoxamine and a MAO inhibitor should be avoided. Wait at
least two weeks after discontinuing an MAO inhibitor before initiating therapy with fluvoxamine. Wait at least
two weeks after discontinuing fluvoxamine before initiating therapy with a MAO inhibitor.
7) Probable Mechanism: serotonin reuptake inhibition
8) Literature Reports
a) Concomitant use of serotonin specific reuptake inhibitors and monoamine oxidase inhibitors can
produce a toxic reaction known as serotonin syndrome (Sternbach, 1991h). Serotonin syndrome is a
condition of serotonergic hyperstimulation and manifests as restlessness, myoclonus, changes in
mental status, hyperreflexia, diaphoresis, shivering, and tremor. If the syndrome is not recognized and
correctly treated, death can result.
b) A 26-year old woman who had been taking isocarboxazid for eight weeks stopped taking the drug
for 11 days before beginning therapy with sertraline. After a single 100 mg sertraline dose, the patient
became restless and developed leg twitches. The patients was later admitted to the emergency room
with diaphoresis, tachycardia, hyperreflexia, and various neuromuscular disturbances. After treatment
with diazepam and propranolol the patient did not improve. The patient was then given two 4 mg doses
of cyproheptadine an hour apart, with notable improvement in symptoms after the second dose (Lappin
& Auchincloss, 1994j).
c) A drug interaction occurred in a 61-year old woman whose regimen of sertraline 100 mg twice daily
was added to a regimen of lithium, phenelzine, thioridazine, and doxepin. Three hours after taking the
first sertraline dose, the patient was found in a semicomatose state, with elevated body temperature,
increased pulse, increased respiration rate, and a blood pressure of 140/110 mm Hg. After
transportation to the hospital, the patient was misdiagnosed as having neuroleptic malignant syndrome
(NMS) which was later changed to serotonin syndrome due to a reaction between sertraline and
phenelzine. The authors suggest that monoamine oxidase inhibitor (MAOI) therapy should be
discontinued for at least two weeks before initiation of therapy with a selective serotonin reuptake
inhibitor (SSRI) and that before starting a MAOI, SSRI therapy should be discontinued for at least five
half-lives of the parent drug and any active metabolites (Graber et al, 1994j).
d) Two cases reports suggested a possible interaction between fluoxetine and selegiline (Suchowersky
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 114
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof115
of 160
Page 115
244
& de Vries, 1990j). One case involved a first episode of mania being observed approximately one month
after adding selegiline to fluoxetine therapy. The patient improved two months after both drugs were
discontinued, and no further details were provided. The second case involved diaphoresis,
vasoconstriction, and cyanosis of the hands which occurred in close temporal relationship to adding
fluoxetine and selegiline. Both drugs were discontinued, with relatively quick resolution of symptoms.
Rechallenge with fluoxetine alone occurred without incident.
3.5.1.FT Tramadol
1) Interaction Effect: an increased risk of seizures and serotonin syndrome (hypertension, hyperthermia,
myoclonus, mental status changes)
2) Summary: Seizures and serotonin syndrome have been reported in patients using tramadol. The risk of
seizures and serotonin syndrome may be enhanced when fluvoxamine and tramadol therapy are combined
(Prod Info Ultram(R), 2001).
3) Severity: major
4) Onset: rapid
5) Substantiation: theoretical
6) Clinical Management: Caution should be used if tramadol is to be administered to patients receiving
concomitant fluvoxamine therapy. If possible, avoid this combination, especially in patients with underlying
conditions that might predispose to seizures. Observe the patient closely for signs and symptoms of
serotonin syndrome.
7) Probable Mechanism: increased concentration of serotonin in the nervous system and periphery
3.5.1.FU Tranylcypromine
1) Interaction Effect: CNS toxicity or serotonin syndrome (hypertension, hyperthermia, myoclonus, mental
status changes)
2) Summary: Concurrent administration or overlapping therapy with fluvoxamine and a monoamine oxidase
(MAO) inhibitor may result in CNS toxicity or serotonin syndrome, a hyperserotonergic state characterized
by symptoms such as restlessness, myoclonus, changes in mental status, hyperreflexia, diaphoresis,
shivering, and tremor. Serious, even fatal, reactions have been reported with concomitant use of serotonin
specific reuptake inhibitors and MAO inhibitors (Prod Info Luvox(R), 1997a; Lappin & Auchincloss, 1994a;
Graber et al, 1994a; Suchowersky & de Vries, 1990a). Concomitant use is not recommended.
3) Severity: major
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Concurrent use of a selective serotonin reuptake inhibitors, such as fluvoxamine,
and tranylcypromine is contraindicated. Wait at least two weeks after discontinuing an MAO inhibitor before
initiating therapy with fluvoxamine. Wait at least two weeks after discontinuing fluvoxamine before initiating
therapy with a MAO inhibitor.
7) Probable Mechanism: serotonin reuptake inhibition
8) Literature Reports
a) Concomitant use of serotonin specific reuptake inhibitors and monoamine oxidase inhibitors can
produce a toxic reaction known as serotonin syndrome (Sternbach, 1991). Serotonin syndrome is a
condition of serotonergic hyperstimulation and manifests as restlessness, myoclonus, changes in
mental status, hyperreflexia, diaphoresis, shivering, and tremor. If the syndrome is not recognized and
correctly treated, death can result.
b) A 26-year old woman who had been taking isocarboxazid for eight weeks stopped taking the drug
for 11 days before beginning therapy with sertraline. After a single 100 mg sertraline dose, the patient
became restless and developed leg twitches. The patients was later admitted to the emergency room
with diaphoresis, tachycardia, hyperreflexia, and various neuromuscular disturbances. After treatment
with diazepam and propranolol the patient did not improve. The patient was then given two 4 mg doses
of cyproheptadine an hour apart, with notable improvement in symptoms after the second dose (Lappin
& Auchincloss, 1994).
c) A drug interaction occurred in a 61-year old woman whose regimen of sertraline 100 mg twice daily
was added to a regimen of lithium, phenelzine, thioridazine, and doxepin. Three hours after taking the
first sertraline dose, the patient was found in a semicomatose state, with elevated body temperature,
increased pulse, increased respiration rate, and a blood pressure of 140/110 mm Hg. After
transportation to the hospital, the patient was misdiagnosed as having neuroleptic malignant syndrome
(NMS) which was later changed to serotonin syndrome due to a reaction between sertraline and
phenelzine. The authors suggest that monoamine oxidase inhibitor (MAOI) therapy should be
discontinued for at least two weeks before initiation of therapy with a selective serotonin reuptake
inhibitor (SSRI) and that before starting a MAOI, SSRI therapy should be discontinued for at least 5
half-lives of the parent drug and any active metabolites (Graber et al, 1994).
d) Two cases reports suggested a possible interaction between fluoxetine and selegiline (Suchowersky
& de Vries, 1990). One case involved a first episode of mania being observed approximately one month
after adding selegiline to fluoxetine therapy. The patient improved two months after both drugs were
discontinued, and no further details were provided. The second case involved diaphoresis,
vasoconstriction, and cyanosis of the hands which occurred in close temporal relationship to adding
fluoxetine and selegiline. Both drugs were discontinued, with relatively quick resolution of symptoms.
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 115
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof116
of 160
Page 116
244
Rechallenge with fluoxetine alone occurred without incident.
3.5.1.FV Triazolam
1) Interaction Effect: elevated serum triazolam concentrations
2) Summary: Fluvoxamine coadministration (100 mg daily) with alprazolam 1 mg four times daily resulted in
a 2-fold increase in alprazolam steady-state plasma concentrations, AUC, Cmax, and half-life. Elevated
plasma levels of alprazolam were associated with impaired psychomotor performance and memory. This
suggests that fluvoxamine is a potent inhibitor of cytochrome P450 3A4 enzymes, which are responsible for
alprazolam metabolism. Because triazolam also relies on CYP3A4 for metabolism, a similar interaction with
fluvoxamine seems likely (Prod Info Luvox(R), 1997d).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When triazolam and fluvoxamine are coadministered, monitor patients for
benzodiazepine toxicity (sedation, lethargy, slurred speech). Triazolam doses may need to be reduced, or
consider switching to a benzodiazepine eliminated by glucuronidation (eg, lorazepam, oxazepam,
temazepam).
7) Probable Mechanism: inhibition of triazolam metabolism and clearance due to cytochrome P450 3A4
enzyme inhibition
3.5.1.FW Tryptophan
1) Interaction Effect: severe vomiting
2) Summary: Tryptophan enhances the serotonergic effect of fluvoxamine and has been reported to cause
severe vomiting. Use the combination cautiously (Prod Info Luvox(R), 1997i).
3) Severity: moderate
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Concurrent use of fluvoxamine and tryptophan should be avoided.
7) Probable Mechanism: enhanced serotonergic effects
3.5.1.FX Valdecoxib
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.1.FY Warfarin
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and anticoagulants has been associated
with an increased risk of bleeding (Wallerstedt et al, 2009; Schalekamp et al, 2008; Prod Info LUVOX(R) CR
extended-release oral capsules, 2008). Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages. Altered anticoagulant effects (including increased
bleeding) have been reported with the coadministration of SSRIs with warfarin. In patients receiving warfarin
and fluvoxamine concomitantly for 2 weeks, warfarin plasma concentrations increased by 98% and
prothrombin times were prolonged. Fluvoxamine appears to inhibit several cytochrome P450 isoenzymes
which may include 1A2 and 2C9 isozymes, which are responsible for warfarin metabolism (Schalekamp et
al, 2008; Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 116
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof117
of 160
Page 117
244
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: When fluvoxamine and an anticoagulant are given concurrently, monitor patient for
signs of increased bleeding. Patients who are taking warfarin should be monitored closely for altered
anticoagulant effects, including increased bleeding, when fluvoxamine therapy is initiated or discontinued.
Periodically reassess the prothrombin time ratio and INR in patients receiving fluvoxamine and anticoagulant
therapy (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
7) Probable Mechanism: unknown
8) Literature Reports
a) According to a retrospective cohort study (n=234), there was an increased risk of clinically relevant
bleeding (hospital admission due to bleeding) in patients receiving warfarin for atrial fibrillation during
concomitant SSRI therapy or within 2 weeks following SSRI therapy termination. Patients with a mean
age of 72 +/- 7 years receiving warfarin plus SSRI (n=117) were matched with randomly selected
patients who received warfarin only (n=117). SSRI included fluoxetine, citalopram, paroxetine,
sertraline, fluvoxamine, or escitalopram. Nine patients experienced 11 bleeding episodes during 213.9
treatment years in the warfarin plus SSRI group, and 10 patients experienced 14 bleedings during 586.4
treatment years in the warfarin-only group. The corresponding total incidences of bleedings were 51.4
and 23.9 per 1000 treatment years, respectively. The hazard ratio for first bleedings during treatment
with warfarin plus SSRI was 3.49 (95% CI; 1.37 to 8.91, p=0.009) compared with warfarin only. The
SSRI implicated in patients experiencing bleeding at the time of concomitant administration were
sertraline or citalopram. The addition of an SSRI was not associated with a change in warfarin dose or
INR (p=0.48 and p=0.31 respectively). The results of the study may be limited by earlier bleeding
events, unknown patient adherence, and exclusion of clopidogrel, dipyridamol, corticosteroids and
anticoagulants other than warfarin in the model (Wallerstedt et al, 2009).
b) A population-based, case-controlled study of new coumarin users (acenocoumarol and
phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an
increased risk of hospitalization due to nongastrointestinal bleeding. Using national pharmacy and
hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal
bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of
treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for
hospitalization for nongastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval
(CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was
not significantly different (Schalekamp et al, 2008).
c) A hospitalized 80-year-old female was started on intravenous heparin and oral warfarin therapy due
to an embolic stroke secondary to atrial fibrillation and mitral stenosis. Her warfarin dose was
maintained at 1 mg daily, with her INR between 2.5 and 3. Fluvoxamine 25 mg daily was started for
depression, and her warfarin dose was increased to 1.5 mg daily 3 days later due to worsening of the
left hemiparesis. Three days later, her INR was 9.96, and a repeat INR to rule out laboratory error was
11.3. Warfarin was discontinued, fresh frozen plasma was given, and fluvoxamine was discontinued.
Six days later, warfarin was again started at 1 mg daily, and the INR increased over 4 days to 11.8. The
elevated INR was attributed to the persisting effect of fluvoxamine. She was eventually stabilized on
warfarin 1 mg daily with INR values between 2 and 2.5 (Yap & Low, 1999).
3.5.1.FZ Xemilofiban
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and antiplatelet agents has been associated
with an increased risk of bleeding. Bleeding events reported have included epistaxis, ecchymosis,
hematoma, petechiae, and life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008;
Prod Info PROZAC(R) oral capsules, delayed-release capsules, solution, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an antiplatelet agent are given concurrently, monitor patient for
signs of increased bleeding (Prod Info PAXIL(R) oral tablets, suspension, 2008; Prod Info PROZAC(R) oral
capsules, delayed-release capsules, solution, 2008)
7) Probable Mechanism: unknown
3.5.1.GA Zolmitriptan
1) Interaction Effect: an increased risk of serotonin syndrome
2) Summary: There have been case reports of weakness, hyperreflexia, and incoordination following
concomitant use of sumatriptan, a 5-hydroxytryptamine-1 (5HT-1) agonist, and a serotonin specific reuptake
inhibitor (SSRI) (Prod Info Imitrex(R), 1998a; Prod Info Zomig(TM), 1997). Because zolmitriptan is a 5HT
1B/1D agonist, a similar interaction between SSRIs and zolmitriptan may occur (Prod Info Zomig(TM),
1997). Concurrent use of zolmitriptan and an SSRI may result in serotonin syndrome which may be lifethreatening. Symptoms of serotonin syndrome may include restlessness, hallucinations, loss of coordination,
fast heart beat, rapid changes in blood pressure, increased body temperature, overreactive reflexes,
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 117
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof118
of 160
Page 118
244
nausea, vomiting, and diarrhea. Clinicians should be aware that triptans may be commonly used
intermittently and that either the triptan or the SSRI may be prescribed by a different physician. Discuss the
risks of serotonin syndrome with patients who are prescribed this combination and monitor them closely for
symptoms of serotonin syndrome (US Food and Drug Administration, 2006).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Coadministration of a triptan, such as zolmitriptan, and an SSRI may result in a
life-threatening condition called serotonin syndrome. Be aware that triptans may be commonly used
intermittently and that either the triptan or the SSRI may be prescribed by a different physician. If these
agents are used together, discuss the risks of serotonin syndrome with the patient and monitor closely for
symptoms of serotonin syndrome (restlessness, hyperthermia, hyperreflexia, incoordination).
7) Probable Mechanism: additive pharmacologic effects resulting in excessive serotonergic stimulation
8) Literature Reports
a) The pharmacokinetics of a single 10 mg dose of zolmitriptan were not altered by four weeks of
fluoxetine 20 mg daily pretreatment in healthy volunteers. The effects of zolmitriptan on blood pressure
were also not changed by fluoxetine therapy (Prod Info Zomig(R), 2002).
3.5.1.GB Zomepirac
1) Interaction Effect: an increased risk of bleeding
2) Summary: The release of serotonin by platelets is important for maintaining hemostasis. Case-control
and cohort studies have shown that the combined use of SSRIs and NSAIDs has been associated with an
increased risk of bleeding. Bleeding events have included epistaxis, ecchymosis, hematoma, petechiae, and
life-threatening hemorrhages (Prod Info PAXIL(R) oral tablets, suspension, 2008) (Prod Info Lexapro(TM),
2003; Dalton et al, 2003a; Prod Info CELEXA (R) oral tablet, solution, 2005).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: When an SSRI and an NSAID are given concurrently, monitor patient for signs of
increased bleeding.
7) Probable Mechanism: unknown
8) Literature Reports
a) SSRIs increase the risk of upper gastrointestinal bleeding and this effect is potentiated by concurrent
use of NSAIDs or low-dose aspirin. Hospitalizations for upper gastrointestinal bleeding were searched
among 26,005 users of antidepressant medications and compared with the number of hospitalizations
in those patients who did not receive prescriptions for antidepressants. The amount of upper GI
bleeding episodes was 3.6 times more than expected (95% confidence interval, 2.7 to 4.7). Combined
use of an SSRI and NSAIDs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1
to 19.5) and 5.2 (95% confidence interval, 3.2 to 8), respectively. The findings of this study demonstrate
an increased risk of upper GI bleeding during the use of SSRIs. Combined use of SSRIs and NSAIDs or
low-dose aspirin increased the risk even further (Dalton et al, 2003).
b) Coadministration of ketorolac with psychoactive drugs (such as fluoxetine) has been associated with
hallucinations in some patients (Prod Info TORADOL(R) oral tablets, 2007).
3.5.2 Drug-Food Combinations
3.5.2.A Grapefruit Juice
1) Interaction Effect: increased fluvoxamine exposure
2) Summary: Grapefruit juice significantly increased fluvoxamine exposure when co-administered to healthy
volunteers (n=10), in a randomized, placebo-controlled crossover study. Compared with baseline, grapefruit
juice produced a 1.3-fold increase in the serum mean concentration of fluvoxamine, by 33
nanograms/milliliter (ng/mL; plus/minus 10 to 44 ng/mL) (p=0.049) and increased the fluvoxamine mean
area under the concentration-time curve from 550 ng hours/mL to 881 ng hours/mL (p=0.014) (Hori et al,
2003a).
3) Severity: minor
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Counsel patients to avoid grapefruit juice while taking fluvoxamine. Orange juice
may be substituted as it provides the same basic nutrients but is not known to inhibit drug metabolism.
7) Probable Mechanism: inhibition of intestinal CYP3A4 and P-glycoprotein-mediated fluvoxamine
metabolism
8) Literature Reports
a) Grapefruit juice significantly increased exposure to fluvoxamine, when co-administered to healthy
volunteers. In a randomized, crossover study, healthy men (n=10) received 250 milliliters of either
regular-strength grapefruit juice or water 3 times daily for 5 days. On day 6, oral fluvoxamine 75
milligrams was given to each subject along with the grapefruit juice or water regimen. Serial blood
sampling then occurred over the next 24 hours. After 2 weeks, subjects crossed over to the opposing
study arm. Compared with baseline, grapefruit juice produced a 1.3-fold increase in the mean serum
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 118
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof119
of 160
Page 119
244
concentration of fluvoxamine, by 33 nanograms/milliliter (ng/mL; plus/minus 10 to 44 ng/mL) (p=0.049).
In 8 subjects, the fluvoxamine mean area under the concentration-time curve increased from 550 ng
hours/mL to 881 ng hours/mL (p=0.014); additionally, 2 subjects showed a rebound increase in
fluvoxamine plasma concentration at 24 hours after fluvoxamine administration (Hori et al, 2003).
3.5.4 Drug-Tobacco Combinations
3.5.4.A Tobacco
1) Interaction Effect: increased fluvoxamine metabolism
2) Summary: In comparison to nonsmokers, fluvoxamine metabolism is increased by 25% in smokers (Prod
Info Luvox(R), 1997ab).
3) Severity: minor
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Monitor fluvoxamine efficacy in patients who smoke. Larger doses of fluvoxamine
may be required.
7) Probable Mechanism: hepatic enzyme induction
4.0 Clinical Applications
Monitoring Parameters
Patient Instructions
Place In Therapy
Mechanism of Action / Pharmacology
Therapeutic Uses
Comparative Efficacy / Evaluation With Other Therapies
4.1 Monitoring Parameters
A) Fluvoxamine Maleate
1) Therapeutic
a) Decreases in depressive or obsessive-compulsive behavior by both subjective and objective
assessments.
2) Toxic
a) Laboratory Parameters
1) Regularly monitor serum electrolytes, especially sodium, blood urea nitrogen, and serum creatinine
in the following patients or disease states (Prod Info fluvoxamine maleate oral tablets, 2005):
elderly
concomitant diuretics
syndrome of inappropriate secretion of antidiuretic hormone
displacement syndromes
edematous states
adrenal disease
fluid depleted patients
b) Physical Findings
1) Monitor patients receiving antidepressants for worsening of depression, suicidality, or unusual
changes in behavior, especially at the initiation of therapy or when the dose increases or decreases.
Such monitoring should include at least weekly face-to-face contact with patients or their family
members or caregivers during the initial 4 weeks of treatment, then visits every other week for the next
4 weeks, then at 12 weeks, and then as clinically indicated beyond 12 weeks. Families and caregivers
should be advised of the need for close observation (i.e., daily observation) of patients and
communication with the prescriber (Prod Info fluvoxamine maleate oral tablets, 2005).
2) Patients who experience symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility,
impulsivity, akathisia, hypomania, or mania may be at an increased risk for worsening depression or
suicidality. If these symptoms are observed, therapy should be re-evaluated and it may be necessary to
discontinue medications when symptoms are severe, sudden in onset, or were not part of the patient's
initial symptoms (Prod Info fluvoxamine maleate oral tablets, 2005).
3) Nausea and/or vomiting seen early during fluvoxamine therapy may be alleviated by reducing the
dose and then gradually increasing the dose to therapeutic effect.
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 119
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof120
of 160
Page 120
244
4.2 Patient Instructions
A) Fluvoxamine (By mouth)
Fluvoxamine
Treats symptoms of obsessive compulsive disorder (OCD) and social anxiety disorder (social phobia).
When This Medicine Should Not Be Used:
You should not use this medicine if you have had an allergic reaction to fluvoxamine. You should not use
fluvoxamine if you are also using alosetron (Lotronex®), thioridazine (Mellaril®), terfenadine (Seldane®),
astemizole (Hismanal®), cisapride (Propulsid®), pimozide (Orap®), or tizanidine (Zanaflex®). Make sure your
doctor knows if you have taken an MAO inhibitor (such as isocarboxazid, phenelzine, selegiline, tranylcypromine,
Eldepryl®, Nardil®, Marplan®, or Parnate®) within the past 2 weeks.
How to Use This Medicine:
Long Acting Capsule, Tablet
Your doctor will tell you how much of this medicine to use and how often. Your dose may need to be
changed several times in order to find out what works best for you. Do not use more medicine or use it more
often than your doctor tells you to.
You may take this medicine with or without food.
Take this medicine at bedtime, unless your doctor tells you otherwise.
Do not use this medicine for longer than 10 weeks unless your doctor tells you otherwise.
Swallow the extended-release capsule whole. Do not crush, break, or chew it.
This medicine should come with a Medication Guide. Read and follow these instructions carefully. Ask your
doctor or pharmacist if you have any questions. Ask your pharmacist for the Medication Guide if you do not
have one. Your doctor might ask you to sign some forms to show that you understand this information.
If a Dose is Missed:
If you miss a dose or forget to use your medicine, use it as soon as you can. If it is almost time for your next
dose, wait until then to use the medicine and skip the missed dose. Do not use extra medicine to make up
for a missed dose.
How to Store and Dispose of This Medicine:
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light.
Ask your pharmacist, doctor, or health caregiver about the best way to dispose of any outdated medicine or
medicine no longer needed.
Keep all medicine away from children and never share your medicine with anyone.
Drugs and Foods to Avoid:
Ask your doctor or pharmacist before using any other medicine, including over-the-counter medicines, vitamins,
and herbal products.
There are many other drugs that can interact with fluvoxamine. Make sure your doctor knows about ALL
other medicines you are using, especially medicines to treat depression or mental illness.
Tell your your doctor if you are using blood thinners (warfarin or Coumadin®), diuretics (water pills), or pain
or arthritis medicine (sometimes called “NSAIDs”) such as aspirin, ibuprofen, Aleve®, or Motrin®. Tell your
doctor if you use a tranquilizer or sedative such as alprazolam (Xanax®), diazepam (Valium®), midazolam
(Versed®), ramelteon (Rozerem®), or triazolam (Halcion®).
Your doctor should know if you use blood pressure medicine (such as atenolol, metoprolol, propranolol,
Corgard®, Inderal®, Lopressor®, Toprol®, or Tenormin®) or medicine to treat headaches (such as
eletriptan, sumatriptan, Imitrex®, or Relpax®).
Tell your doctor if you also use carbamazepine (Tegretol®), clozapine (Clozaril®), diltiazem (Cardizem®),
linezolid (Zyvox®), lithium (Eskalith®), methadone (Dolophine®), mexiletine (Mexitil®), quinidine,
omeprazole (Prilosec®), phenytoin (Dilantin®), St. John's wort, Tacrine (Cognex®), theophylline (TheoDur®), tramadol (Ultram®), or tryptophan supplements.
Do not drink alcohol while you are using this medicine.
Warnings While Using This Medicine:
Make sure your doctor knows if you are pregnant or breastfeeding, or if you have diabetes, liver disease,
heart disease or a recent heart attack, epilepsy or seizures, bleeding problems, or a history of mania. Tell
your doctor if you smoke.
For some children, teenagers, and young adults, this medicine can increase thoughts of suicide. Tell your
doctor or your child's doctor right away if you or your child start to feel more depressed and have thoughts
about hurting yourselves. Report any unusual thoughts or behaviors that trouble you or your child, especially
if they are new or are getting worse quickly. Make sure the doctor knows if you or your child have trouble
sleeping, get upset easily, have a big increase in energy, or start to act reckless. Also tell the doctor if you or
your child have sudden or strong feelings, such as feeling nervous, angry, restless, violent, or scared. Let
the doctor know if you, your child, or anyone in your family has bipolar disorder (manic-depressive) or has
tried to commit suicide.
While you are using this medicine, be sure to keep all appointments with your caregiver or mental health
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 120
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof121
of 160
Page 121
244
counselor. It is very important that your caregivers observe you for changes in your mental status or
behavior.
Fluvoxamine should not be used to treat depression. It should not be given to a child unless that child has
been diagnosed with OCD.
This medicine may make you dizzy or drowsy. Avoid driving, using machines, or doing anything else that
could be dangerous if you are not alert.
Do not stop using this medicine suddenly without asking your doctor. You may need to slowly decrease your
dose before stopping it completely.
Possible Side Effects While Using This Medicine:
Call your doctor right away if you notice any of these side effects:
Allergic reaction: Itching or hives, swelling in your face or hands, swelling or tingling in your mouth or throat,
chest tightness, trouble breathing.
Anxiety, agitation, aggression, trouble sleeping, or panic attack.
Blurred vision, shallow breathing, trouble standing or walking.
Change in how much or how often you urinate.
Chest pain.
Confusion, extreme weakness, muscle twitching.
Fast, slow, or uneven heartbeat.
Feeling irritable, nervous, or shaky.
Fever, chills, cough, sore throat, and body aches.
Lightheadedness or fainting.
Numbness, tingling, or burning pain in your hands, arms, legs, or feet.
Seizures or tremors.
Sudden and severe stomach pain, nausea, or vomiting.
Swelling in your hands, feet, or ankles.
Unusual behavior, thoughts of hurting yourself or others.
Unusual bleeding or bruising.
Yellowing of your skin or the whites of your eyes.
If you notice these less serious side effects, talk with your doctor:
Diarrhea, constipation, stomach upset, or loss of appetite.
Dry mouth.
Headache or dizziness.
Mood or behavior changes after you stop using the medicine.
Muscle pain.
Pain during monthly periods.
Problems having sex.
Prolonged erection of the penis.
Skin rash.
Sleepiness.
Sweating more than usual.
Weakness.
If you notice other side effects that you think are caused by this medicine, tell your doctor.
4.3 Place In Therapy
A) Fluvoxamine Maleate
1) Obsessive-compulsive Disorder
a) The extended-release formulation of fluvoxamine maleate is indicated for the treatment of obsessions
and compulsions in adult patients with obsessive compulsive disorder (OCD) (Prod Info LUVOX(R) CR
extended-release oral capsules, 2008), and the immediate-release formulation of fluvoxamine maleate is
indicated for the treatment of obsessions and compulsions in patients with OCD aged 8 years and older
(Prod Info LUVOX(R) oral tablets, 2007).
b) Treatment with extended-release fluvoxamine maleate at once-daily doses of 100 to 300 milligrams was
safe and led to clinical improvement in adult patients with obsessive-compulsive disorder compared to
placebo in a 12-week, multicenter, randomized, double-blind study (n=253) (Hollander et al, 2003).
c) A 10-week study demonstrated that immediate-release fluvoxamine and behavior therapy were more
efficacious for treating obsessive compulsive disorder (OCD) compared to placebo and behavior therapy
(Hohagen et al, 1998).
d) Immediate-release fluvoxamine was significantly more effective than placebo in children (8 years or
older) and adolescents with obsessive compulsive disorder (OCD) in a 10-week, double-blind study in 120
children with at least a 6-month history of OCD (Riddle, 1996).
2) Social Anxiety Disorder
a) Extended-release fluvoxamine maleate is indicated for social anxiety disorder, also known as social
phobia (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
b) In a randomized, double-blind, multicenter, placebo-controlled study (n=300), patients with generalized
social anxiety disorder (GSAD) who received fluvoxamine extended-release (ER) demonstrated a
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 121
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof122
of 160
Page 122
244
significantly greater reduction in the mean Liebowitz Social Anxiety Scale (LSAS) total score from baseline
compared with patients who received placebo (Westenberg et al, 2004), with a trend towards continued
clinical benefit with fluvoxamine ER compared to placebo in a 12-week double-blind extension phase of this
study (Stein et al, 2003).
3) Depression
a) All of the selective serotonin reuptake inhibitors (SSRIs) are effective for treating depression, although
selected characteristics of each agent may offer greater benefit in some patients. Fluvoxamine does not
have any major therapeutic benefits over other SSRIs; however, discontinuation of therapy among patients
treated with fluvoxamine appeared higher than for other SSRIs during clinical trials. Gastrointestinal
symptoms and drowsiness/sedation were more common especially early in therapy than with other SSRIs.
Ultimately, the selection of an SSRI is dependent on clinical judgement and response of patients to previous
therapy (Edwards & Anderson, 1999).
b) Data suggest that a trial of a second serotonin reuptake inhibitor (SSRI) is a viable clinical alternative in
depressed patients who have failed to respond to an adequate trial of the first SSRI used. In a retrospective
review of 55 patients who had failed to respond to at least five weeks of therapy with either fluoxetine,
sertraline, fluvoxamine, or paroxetine (all at therapeutic dosages), 51% responded to a trial of an alternative
agent. The choice of the second agent was based on clinician preference; no difference between response
rates of the different drugs was noted (Joffe et al, 1996).
4.4 Mechanism of Action / Pharmacology
A) Fluvoxamine Maleate
1) Mechanism of Action
a) Fluvoxamine maleate is a potent selective serotonin (5-HT) reuptake inhibitor (SSRI) belonging to the 2aminoethyl oxime ethers of aralkylketones series and is unrelated to other SSRIs and clomipramine. In
obsessive compulsive disorder the clinical effect is presumed to be from its specific inhibition of serotonin
reuptake in brain neurons. In-vitro studies have shown that fluvoxamine maleate has no significant affinity
for histaminergic, alpha or beta adrenergic, muscarinic, or dopaminergic receptors (Prod Info LUVOX(R) CR
extended-release oral capsules, 2008; Prod Info LUVOX(R) oral tablets, 2007).
2) Review Articles
a) Fluvoxamine is a compound in the series of 2-aminoethyloxime ethers of aralkylketones. The drug acts
as an antidepressant and has no structural similarities to tricyclic antidepressants. Fluvoxamine is a potent
selective inhibitor of presynaptic serotonin (5-hydroxytryptamine or 5-HT) reuptake (Claassen et al, 1977).
Following a single dose of fluvoxamine, the serotonin turnover in the rat forebrain was reduced (Claassen et
al, 1977). Also, in the raphe nuclei the intraneuronal and extraneuronal concentrations of serotonin
decreased and increased, respectively (Constantinidis et al, 1981). In vitro and in vivo experiments
demonstrated that fluvoxamine fails to facilitate noradrenergic neurotransmission, similar to other specific
inhibitors of serotonin uptake (Bradford, 1983; Claassen, 1983). Unlike the tricyclic antidepressants,
fluvoxamine demonstrates a very low in vitro affinity for alpha-1, alpha-2, beta-1, dopamine-2, histamine-1,
serotonin-1, serotonin-2 or muscarinic receptors (Richelson & Nelson, 1984; Benfield & Ward, 1986). In vitro
and in vivo studies have not demonstrated any monoamine oxidase inhibitor activity (Lapierre et al, 1983;
Benfield & Ward, 1986).
b) The exact relationship of serotonin uptake inhibition and its effects on depression are not known. It is
proposed that fluvoxamine's antidepressant activity is initiated by enhanced serotoninergic input to other
neuronal systems in the brain. This may lead to primary and secondary changes in receptors and rates of
firing and rates of release of neurotransmitters which may result in remission of depressive symptoms (Fuller
& Wong, 1987).
c) The effects of treatment with fluvoxamine on platelet and plasma serotonin were studied in 11 drug-free
patients with major depression (Celeda et al, 1992). Single-dose fluvoxamine (50 mg) was without effect on
serotonin, whereas treatment with 100 to 150 mg/day for 12 weeks reduced both platelet (-89%) and plasma
(-60%) serotonin. Patients who responded to the treatment at 6 weeks had significantly lower pretreatment
values of platelet serotonin than the rest. This suggests that "low serotonin" patients may respond more
rapidly to fluvoxamine. Platelet serotonin and Hamilton Depression Scale scores correlated significantly
during treatment. These data demonstrate a marked action of fluvoxamine as a serotonin reuptake inhibitor
at therapeutic doses and confirm that this mechanism is relevant for its efficacy as an antidepressant.
d) Fluvoxamine does not have significant effects on central norepinephrine function in human depressed
patients, as determined by measurement of MHPG, VMA, NMN, and HVA in urine and NE in plasma
(Johnson et al, 1993).
e) The possible relationship between plasma tryptophan (Trp) to large neutral amino acid (LNAA) ratio,
thought to reflect brain serotonin (5-HT) formation, was estimated in 47 patients with major depression
(unipolar and bipolar) before and after 6 weeks of fluvoxamine. The authors found a significant difference
between responders (n=39) and nonresponders (n=8) for Trp/LNAA ratio, whereas no difference emerged
between the two groups for the mean plasma steady-state fluvoxamine levels. These data suggest that a
specific plasma amino acid profile may be a useful indicator of good clinical response to fluvoxamine (Lucca
et al, 1994).
4.5 Therapeutic Uses
4.5.A Fluvoxamine Maleate
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 122
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof123
of 160
Page 123
244
Alcoholism
Asperger's disorder
Autistic disorder
Body dysmorphic disorder
Compulsive buying
Compulsive exhibitionism
Compulsive gambling
Depression
Eating disorder
Fibromyalgia
Hypochondriasis
Mixed anxiety and depressive disorder
Myocardial infarction; Prophylaxis
Obsessive-compulsive disorder
Panic disorder
Posttraumatic stress disorder
Premenstrual dysphoric disorder
Prostatic pain
Repetitive self-excoriation
Severe major depression with psychotic features
Social phobia
Stereotypy habit disorder
Trichotillomania
Wernicke-Korsakoff syndrome
4.5.A.1 Alcoholism
a) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
Adverse effects limit the usefulness of fluvoxamine for treating alcoholism (Kranzler et al, 1993).
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 123
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof124
of 160
Page 124
244
c) Adult:
1) Adverse effects limit the usefulness of fluvoxamine for treating alcoholism. Results of open-label and
placebo-controlled trials of fluvoxamine as an adjunct to relapse prevention psychotherapy in alcoholics
were reported (Kranzler et al, 1993). In the open trial, 16 inpatient alcoholics began a 12-week
treatment program, with 10 patients dropping out during the first 4 weeks of treatment. In the controlled
trial, 8 of 10 patients on fluvoxamine dropped out during the first 4 weeks of treatment, compared with
only 1 of 9 patients on placebo. Baseline patient characteristics did not explain the baseline differential
attrition in the controlled trial, although the placebo-treated patients are more alcohol-dependent. In both
trials, patients taking fluvoxamine complained of a variety of adverse effects, which they identified as
the basis for early termination of treatment. The most commonly reported adverse effects were nausea,
headache, and sedation. More severe effects included hepatitis (1), depigmenting dermatitis (1), and
focal seizures (1).
4.5.A.2 Asperger's disorder
a) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Pediatric, Evidence is inconclusive
Recommendation: Pediatric, Class IIb
Strength of Evidence: Pediatric, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
Fluvoxamine treatment improved sleep and reduced excessive fears and interests in a case report
of a boy with Asperger's syndrome (Furusho et al, 2001).
c) Pediatric:
1) Fluvoxamine treatment improved sleep and reduced excessive fears and interests of an 8-year-old
boy with Asperger's syndrome, a pervasive developmental disorder with similarities to autism. In
addition to poor sleep, the boy showed an inability to communicate with school classmates and
teachers and displayed anxiety about remembered unpleasant occurrences. Although language
development was normal, he sometimes spoke in a peculiar voice. He was given fluvoxamine 25
milligrams twice daily (after breakfast and supper). Within 4 weeks, his excessive fears and interests
were reduced, his sleep improved, hyperactivity declined, and he gained control over unusual
behaviors, such as using the peculiar voice. After 7 months of treatment, he continued to have some
difficulty communicating with others. No adverse effects were observed (Furusho et al, 2001).
4.5.A.3 Autistic disorder
a) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
In adults, fluvoxamine was more effective than placebo for improving symptoms of autism
(McDougle et al, 1996).
c) Adult:
1) In a 12-week, placebo-controlled trial (n=30), fluvoxamine was more effective than placebo for
reducing repetitive thoughts/behavior and aggression and for improving some aspects of social
interaction and language usage. Patients assigned to fluvoxamine were initially treated with 50
milligrams (mg) per day which was adjusted to a maximum of 300 mg daily over 3 weeks; the dosage
was 276 mg versus 283 mg in patients treated with fluvoxamine versus placebo, respectively, at the
conclusion of the study. Using the Clinical Global Impression Scale, fluvoxamine was statistically
superior to placebo (p less than 0.001); statistically significant differences were also noted for other
assessment scales. In addition, 4 of 15 patients treated with fluvoxamine showed clinically significant
improvements in social functioning, including full-time employment (n=1), participation in a wedding
(n=1), and a move from a group home to a supervised apartment (n=2). Adverse effects were mild and
did NOT require treatment discontinuation. Based on the positive results obtained in these adult
patients with autism, further study is required in children and adolescents with autism (McDougle et al,
1996).
4.5.A.4 Body dysmorphic disorder
a) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
Fluvoxamine produced a significant response in patients with body dysmorphic disorder in an open-
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 124
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof125
of 160
Page 125
244
label study (n=30) (Phillips et al, 2001).
c) Adult:
1) In a 16-week, open-label study, fluvoxamine appeared effective in the treatment of body dysmorphic
disorder (BDD). After establishing the diagnosis of BDD, patients (n=30, 21 females) were treated with
fluvoxamine 50 milligrams (mg) daily with increases to 150 mg twice daily by day 9, if tolerated. Using
an intent-to-treat analysis, it was found that there were statistically significant (p less than 0.001)
decreases in the Brown Assessment of Beliefs Scale (BABS), 66%; the Yale-Brown Obsessive
Compulsive Scale modified for BDD (BDD-YBOCS), 46.6%; the Hamilton Rating Scale for Depression
(HAM-D), 38%; and the Montgomery-Asberg Depression Rating Scale (MADRS), 38%; at study endpoint. Additionally, the Clinical Global Impressions Scale (CGI) rated 63% of patients as responders.
Five of 7 delusional patients were responders; and response was not related to initial severity of illness.
The mean dose of fluvoxamine was 238.3 mg/day (range 50-300 mg/day) and the mean response time
was 6.1 weeks (range, 1 to 16 weeks). Only 60% of the patients completed the study (reasons for dropouts not stated). This preliminary study suggests that fluvoxamine is effective for BDD, but blinded,
placebo-controlled studies are needed to determine efficacy (Phillips et al, 2001).
4.5.A.5 Compulsive buying
a) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Ineffective
Recommendation: Adult, Class III
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
Treatment with fluvoxamine did not alter the buying behavior of subjects prone to compulsive
buying in a randomized, placebo-controlled trial (n=37) (Ninan et al, 2000).
c) Adult:
1) Results of a prospective, randomized, double-blind, placebo- controlled study demonstrated no
benefit with fluvoxamine therapy in the number of shopping episodes, amount of time spent shopping,
amount of money spent, or number of items purchased in 37 subjects with compulsive buying disorder.
Forty-two subjects entered the study beginning with a 1-week single-blind placebo lead-in. Five subjects
who experienced more than a 50% improvement in the Yale-Brown Obsessive Compulsive Scale
modified for compulsive buying (YBOCS-CB) scores after this first week were excluded. Seventy-four
percent of the 42 enrolled patients were diagnosed with comorbid psychiatric disorders. Subjects were
randomized to placebo or daily fluvoxamine 50 milligrams (mg) increased weekly up to 300 mg
according to subject response and tolerance. The average dose of fluvoxamine was 215 mg. The most
commonly reported adverse events with fluvoxamine therapy were gastrointestinal distress (25%) and
insomnia (20%), compared with headache (29%) and sedation (18%) with placebo. Each of the efficacy
variables, YBOCS-CB, Global Assessment of Functioning (GAF), and Hamilton Rating Scale for
Depression (HAM-D) improved with time for both treatment groups, yet no difference between treatment
groups was observed (Ninan et al, 2000).
4.5.A.6 Compulsive exhibitionism
a) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
Fluvoxamine was effective in one case of compulsive exhibitionist behavior (Zohar et al, 1994).
c) Adult:
1) Fluvoxamine was effective in extinguishing inappropriate compulsive exhibitionist behavior in a 36year-old patient who was persistently masturbating in front of women in public. After 2 weeks of
fluvoxamine at a dose of 300 milligrams daily, the behavior and impulses had disappeared completely
(Zohar et al, 1994).
4.5.A.7 Compulsive gambling
a) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
In a small, open study, fluvoxamine reduced pathological gambling (Hollander et al, 1998).
c) Adult:
1) Of 10 patients who completed 8 weeks of fluvoxamine therapy, total abstinence of gambling was
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 125
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof126
of 160
Page 126
244
achieved in 7. Sixteen patients began treatment with placebo for 8 weeks but 4 and 2 were terminated
due to noncompliance and lack of efficacy, respectively. The remaining patients received fluvoxamine;
the mean fluvoxamine dose was 220 milligrams/day at study endpoint. The Yale-Brown scale gambling
behavior scores were reduced by 25%, and 7 of 10 patients were considered treatment responders by
the clinician-rated Clinical Global Impression scores. While fluvoxamine appeared effective, this study
was small, non-blinded, and of short duration; therefore, a randomized, controlled trial is needed to
verify the results (Hollander et al, 1998).
4.5.A.8 Depression
a) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIa
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
Fluvoxamine was more effective than placebo during double-blind trials for the treatment of
depression (Ottevanger, 1994; Martin et al, 1987a) (Porro et al, 1988).
A single night time dose of fluvoxamine appears to be best tolerated (Siddigui et al, 1985).
c) Adult:
1) Fluvoxamine is effective in the treatment of DELUSIONAL DEPRESSION (Gatti et al, 1996). In a
group of 59 patients, 84.2% responded favorably within the six-week study period. The dose of
fluvoxamine used was 100 mg daily days 1 through 3; 200 mg daily days 4 through 7; and 300 mg daily
from day 8. No other psychotropic drugs were used, except for eight patients who continued to receive
maintenance therapy with lithium.
2) Fluvoxamine was effective in the treatment of severely depressed patients in a re-evaluation of a
double-blind study of fluvoxamine, imipramine, and placebo in 308 patients (Ottevanger, 1994).
Improvement was superior in severely depressed patients to that of moderately depressed patients,
which in turn was superior to mildly depressed patients. Anticholinergic side effects were more common
for imipramine, while gastrointestinal effects were more frequent with fluvoxamine.
3) Fluvoxamine was safe and effective for treating depression during a 6-week, large-scale, open trial
of 5625 depressed patients (Martin et al, 1987a). All patients were started on fluvoxamine 50 to 100
milligrams at night, increasing after the first week, if necessary, to a maximum of 300 milligrams per
day. Of the original 5625 patients admitted, 73% completed the study. In 6.4% (358 patients),
withdrawal was not considered to be drug related. Other reasons for withdrawal included adverse
effects in 16.2% (912 patients) and lack of efficacy in 2.1% (117 patients). The most commonly reported
adverse effect was nausea (12.7%), followed by headache (5%), dizziness (4.5%), and somnolence
(3.8%).
4) Fluvoxamine produced a more significant reduction in the global score of the Hamilton Rating Scale
of Depression than placebo during a 4-week, double-blind study of 41 patients with depression (Porro et
al, 1988). Patients randomized to receive fluvoxamine started at doses of 100 milligrams/day and were
increased to 150 milligrams/day after 3 days. A significant reduction in the partial scores connected with
anxiety and depression was observed in the fluvoxamine-treated patients after 7 days of therapy when
compared with baseline scores. This trend became greater during the course of the treatment. Placebotreated patients demonstrated a reduction in anxiety-related scores during the first 7 days; however, this
disappeared over the course of treatment. The most commonly reported adverse effects associated
with fluvoxamine therapy were nausea, vomiting, tremor, dry mouth, and increased salivation; however,
they were only slightly-to-moderately severe and usually resolved by the end of the study.
5) An uncontrolled, non-randomized study of fluvoxamine 100 milligrams/day in 16 depressed HIV-1infected patients revealed that fluvoxamine should not be used as first line treatment in this clinical
setting. Good efficacy was reported in 6 patients, whereas the other 10 discontinued the drug due to
severe adverse effects (acute total insomnia, gastrointestinal disturbance, aggressive and impulsive
behavior, and excessive sedation) (Grassi et al, 1995).
4.5.A.9 Eating disorder
a) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIa
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
In small open-label and larger double-blind, placebo-controlled trials, fluvoxamine has been
effective for reducing the number of binge-eating episodes and for bulimia nervosa (AynsoGutierrez et al, 1994), (Brambilla et al, 1995a; Hudson et al, 1998).
c) Adult:
1) In a 9-week study, fluvoxamine effectively reduced the frequency of binges in patients with bingeeating disorder. In this double-blind, flexible-dose study (n=85), patients were randomly assigned to
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 126
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof127
of 160
Page 127
244
placebo or fluvoxamine 50 milligrams (mg) daily titrated to a maximum dose of 300 mg daily.
Fluvoxamine compared to placebo resulted in a significant reduction in frequency of binges (p=0.006),
Clinical Global Impression severity scale score (p=0.002), and body mass index (p=0.04). Of the 67
patients who completed 9 weeks of treatment, 15 and 12 were in remission (no binges) or markedly
improved (75% or greater improvement) in the fluvoxamine and placebo groups, respectively (p=0.04).
Significantly more patients treated with fluvoxamine than placebo discontinued treatment due to
adverse effects (p=0.03); however, none of the adverse effects were serious. Of interest, the placebo
response was between 42% and 44% which suggests that a conservative approach should be used in
offering drug therapy for this disorder (Hudson et al, 1998).
2) A review article discussing BINGE EATING DISORDER found that fluvoxamine was effective in
isolated cases and a few small trials (Hudson et al, 1996). A significant reduction in the frequency of
binge eating was noted by one investigator in 10 patients who did not self-induce vomiting. This was
conducted over an 8 week course. Another investigator found similar reductions in the frequency of
binge eating episodes, in addition to a significant overall improvement compared to placebo over a 9week course. In a case report, fluvoxamine was effective for binge-eating disorder. A 58-year-old
female sought treatment for binge-eating 4 episodes per week. She suffered from chronic binges for 18
years. Previous unsuccessful therapy included psychotherapy, and over-the-counter appetite
suppressants. Randomized to fluvoxamine 100 milligrams daily, she reported no binge eating episodes
by the second week of therapy. She reported only 1 binge episode during the following seven weeks of
treatment. Her binge eating relapsed after 2 weeks without fluvoxamine. She was unable to restart
fluvoxamine however, as it was not commercially available at the time.
3) Fluvoxamine was effective in the treatment of 20 patients with bulimia nervosa when used in doses
of 50 to 150 mg per day for eight weeks (Aynso-Gutierrez et al, 1994). Four patients showed
drowsiness and 3 insomnia.
4) In an uncontrolled, non-randomized study, 15 women with bulimia nervosa were administered 4
months of combined cognitive-behavioral and nutritional therapy along with either fluvoxamine 300
milligrams (mg) per day or amineptine 300 mg/day. Bulimic Investigation Test symptoms and gravity
improved significantly and equally in both groups, whereas Eating Disorders Inventory scores and
depression and anxiety according to the Hamilton Rating Scale for Depression and Anxiety decreased,
but not significantly. Body mass index was normal before therapy and did not change during treatment.
These preliminary results need to be validated in larger and better designed studies (Brambilla et al,
1995a).
4.5.A.10 Fibromyalgia
a) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
Fluvoxamine may be helpful for patients with fibromyalgia (Nishikai & Akiya, 2003).
c) Adult:
1) Fluvoxamine was equally effective to amitriptyline in reducing pain associated with fibromyalgia. In
an open-label, uncontrolled study, 68 Japanese patients with fibromyalgia received either amitriptyline
at a mean dose of 20 milligrams (mg)/day or fluvoxamine at a mean dose of 25 mg/day for 4 weeks.
Patients evaluated pain relief by means of a visual analog scale and efficacy was defined as a decrease
in pain by at least 50%. At 4 weeks, 50% of patients in the amitriptyline group and 41% of patients in the
fluvoxamine group reported effective relief of pain (p=NS). Drowsiness was the most commonly
reported adverse event with amitriptyline treatment and nausea was most frequently reported with
fluvoxamine. The authors hypothesize that because the efficacy of amitriptyline for the treatment of
fibromyalgia-related pain has been established in previous, controlled trials and because fluvoxamine
showed similar efficacy to amitriptyline in this open-label study; fluvoxamine may be helpful for patients
with fibromyalgia (Nishikai & Akiya, 2003).
4.5.A.11 Hypochondriasis
a) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
Fluvoxamine may be beneficial in the treatment of hypochondriasis (Fallon et al, 2003).
c) Adult:
1) The results of one study suggest that fluvoxamine may be a beneficial treatment in reducing
symptoms of patients with hypochondriasis. In a small, 12-week, open-label study, patients with at least
a moderate hypochondriasis rating on the Heightened Illness Concern Severity Scale (HICSS) received
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 127
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof128
of 160
Page 128
244
daily divided doses of fluvoxamine (50 milligrams (mg) initially, increased every 7 days to a maximum
dose of 300 mg by the sixth week) for 10 weeks following a 2-week placebo run-in phase. Response
was defined as a clinician-rated change in score of "much improved" or "very much improved" on the
Clinical Global Impressions (CGI) scale. In the intent-to-treat analysis, 57.1% of patients responded to
fluvoxamine treatment. In patients who completed 6 or more weeks of treatment, 72.7% were
responders and mean scores on the HICSS were significantly reduced from baseline to endpoint (5 vs
3.64, p=0.001). Fluvoxamine was generally well tolerated. Further, well- controlled studies are needed
to substantiate these findings (Fallon et al, 2003).
4.5.A.12 Mixed anxiety and depressive disorder
a) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
Fluvoxamine was effective for treating depression accompanied by an anxiety disorder in a small,
open-label study (n=30) (Sonawalla et al, 1999).
c) Adult:
1) Eighteen (60%) of 30 patients achieved a score of 2 or less on the Clinical Global ImpressionsImprovement (CGI-I) scale for both anxiety and depression. All patients had major depression with at
least 1 co-morbid anxiety disorder. Fluvoxamine was initiated at 50 milligrams (mg)/day and was titrated
to 200 mg/day as needed and tolerated; the mean dose was 143 mg/day at 12 weeks (study endpoint).
Twenty (67%) and 23 (77%) patients showed a response on the CGI-I depression and CGI-I anxiety
scales at endpoint, respectively. Twelve patients withdrew from the study before 12 weeks. This small
open study suggests that fluvoxamine is effective for treating depression accompanied by an anxiety
disorder, but these results must be confirmed in a controlled clinical trial (Sonawalla et al, 1999).
4.5.A.13 Myocardial infarction; Prophylaxis
a) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class III
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
SSRIs, including fluvoxamine, may confer a protective effect against first MI (Sauer et al, 2001).
c) Adult:
1) In a case-control study comprised of 653 cases of first myocardial infarction (MI) and 2990 control
subjects, results indicated that selective serotonin reuptake inhibitors (SSRIs) may confer a protective
effect against first MI. The subjects in this study were smokers, between the ages of 30 to 65 years,
with a first MI hospitalized between September 1995 and December 1997. The four SSRIs investigated
in this study were fluoxetine, fluvoxamine, paroxetine, and sertraline; doses taken by participants were
not stated. The odds ratio of patients who were taking SSRIs having a first MI compared to controls
(after adjustment for potential confounders) was 0.35 (95% CI 0.18, 0.68; p less than 0.01). The authors
suggested that this effect was possibly attributable to an inhibitory effect on serotonin-medicated
platelet activation or amelioration of other factors associated with increased risk for MI in depression
(Sauer et al, 2001).
4.5.A.14 Obsessive-compulsive disorder
FDA Labeled Indication
a) Overview
FDA Approval: Adult, yes; Pediatric, yes (8 years and older (immediate-release formulation only))
Efficacy: Adult, Effective; Pediatric, Effective
Recommendation: Adult, Class IIa; Pediatric, Class IIa
Strength of Evidence: Adult, Category B; Pediatric, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
The extended-release formulation of fluvoxamine maleate is indicated for the treatment of
obsessions and compulsions in adult patients with obsessive compulsive disorder (OCD) (Prod Info
LUVOX(R) CR extended-release oral capsules, 2008), and the immediate-release formulation of
fluvoxamine maleate is indicated for the treatment of obsessions and compulsions in patients with
OCD aged 8 years and older (Prod Info LUVOX(R) oral tablets, 2007).
A 10-week study demonstrated that immediate-release fluvoxamine and behavior therapy were
more efficacious for treating obsessive compulsive disorder compared to placebo and behavior
therapy (Hohagen et al, 1998).
Immediate-release fluvoxamine was significantly more effective than placebo in children (8 years or
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 128
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof129
of 160
Page 129
244
older) and adolescents with obsessive compulsive disorder (OCD) in a 10-week, double-blind study
in 120 children with at least a 6-month history of OCD (Riddle, 1996).
Treatment with extended-release fluvoxamine maleate at once-daily doses of 100 to 300 milligrams
was safe and led to clinical improvement in adult patients with obsessive-compulsive disorder
compared to placebo in a 12-week, multicenter, randomized, double-blind study (n=253) (Hollander
et al, 2003).
c) Adult:
1) General Information
a) Of the selective serotonin reuptake inhibitors (SSRIs) (ie, fluoxetine, sertraline, paroxetine,
fluvoxamine) with U.S. Food and Drug Administration approval for treating OCD, all are effective.
Limited clinical studies also suggest that the SSRIs are comparable to clomipramine; however,
results of a meta-analysis found that clomipramine may be more effective than the SSRIs (Flament
& Bisserbe, 1997; Leonard, 1997). Selection of initial treatment is often based on the side effect
profile of the individual drug; in general, the SSRIs are tolerated better than clomipramine (Leonard,
1997). Early studies used near maximal doses of an SSRI which resulted in a high incidence of
adverse effects; however, initial low doses with gradual dose adjustment result in a good response
in some patients and better tolerance in most (Leonard, 1997). While the optimal duration of
treatment has NOT been defined, most patients require long-term treatment. A few small studies
have shown relapse rates between 65% and 90% when pharmacologic treatment was stopped
(Rasmussen & Eisen, 1997). Patients who do NOT respond to 10 to 12 weeks of maximum doses
of an SSRI and/or behavioral therapy are considered refractory to treatment. In about 20% of this
group, a trial of a second SSRI will be effective. In the remaining patients, augmentation therapy
with haloperidol or clonazepam may be beneficial (Rasmussen & Eisen, 1997).
2) Clinical Trials
a) Immediate-release Formulation
1) Fluvoxamine and behavior therapy are efficacious for treating obsessive compulsive
disorder (OCD). Patients were randomized to receive fluvoxamine 300 milligrams (mg) daily,
initiated at doses of 50 mg daily and titrated as tolerated in 50 mg increments weekly, and
behavior therapy (n=24) or placebo and behavior therapy (n=25). After 10 weeks of treatment,
both groups showed significant improvements in scores on the Structured Clinical Interview
(SCID), Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Hamilton Depression Scale
(HAM-D), Clinical Anxiety Scale (CAS), Global Assessment Scale (GAS), and the Clinical
Global Improvement Scale (CGIS). Fluvoxamine and behavioral therapy were significantly
more effective in treating obsessions than placebo and behavior therapy, as defined by
improvements in total Y-BOCS scores and Y-BOCS obsession scores. Treatment with
fluvoxamine and behavior therapy also showed a significantly greater improvement than
placebo and behavior therapy in patients with secondary depression. Treatment with
fluvoxamine and behavior therapy may be advantageous in patients whose obsessions, not
compulsions, dictate their clinical profile and for patients that have depression secondary to
OCD (Hohagen et al, 1998).
2) Data from small, short-term or non-blinded studies indicate that patients with obsessivecompulsive disorder (OCD) may tolerate substantial reductions in fluvoxamine dosage without
a relapse (Mundo et al, 1997; Ravizza et al, 1996). In a double-blind study, patients with stable
OCD tolerated reductions in the dosage of fluvoxamine or clomipramine of 33% to 67% without
relapses for up to 102 days. Thirty patients were randomly assigned to group I (same dosage),
group II (33% to 40% reduction in dosage), or group III (60% to 67% reduction in dosage). Five
patients relapsed during the study; 3 were in the control group, and 1 each was in groups II
and III. No statistical difference was identified between treatment groups for the cumulative
number of patients who completed the study without a relapse. Larger studies are needed to
confirm these results (Mundo et al, 1997).
3) Long-term outcome at 18 months posttreatment favored exposure therapy with or without
fluvoxamine for treating OCD. Drug effects did not last while exposure therapy did. At 18
months, a smaller number of exposure therapy patients were receiving antidepressant
treatment, but all three groups showed comparable improvement. Sixty outpatients with OCD
treated for six months with either 1) fluvoxamine and antiexposure therapy (F), 2) fluvoxamine
and exposure therapy (FE), or 3) placebo and exposure therapy (PE) (20 patients per group)
were followed up one year after these treatments were stopped to determine their clinical
status. Fluvoxamine dosage ranged up to 300 mg per day, and the drug was taken for 24
weeks. It was gradually tapered from week 24 to 28. Antiexposure therapy was a mild form of
behavior therapy using relaxation instead of confrontation with feared situations. Thirty-three of
60 patients were rated at 18 months. FE and F produced a greater reduction in rituals at 8
weeks and in depression at 24 weeks than did PE, but this difference disappeared at 12
months (Cottraux et al, 1993).
4) OCD patients with co-morbid chronic tic disorder may require addition of a neuroleptic to
fluvoxamine for effective symptom reduction (McDougle et al, 1994). A 25-year-old male
patient with a history of Tourette's syndrome was treated with fluvoxamine for OCD symptoms.
Fluvoxamine worsened tics, led to coprolalia (use of feces-related foul language) and did not
help the OCD. The addition of pimozide dramatically reduced both the OCD and Tourette's
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 129
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof130
of 160
Page 130
244
symptoms. Double-blind sequential discontinuation of fluvoxamine and pimozide confirmed
that pimozide alone reduced only tics and the combination of fluvoxamine and pimozide was
required for improvement in OCD. Tics may reflect a subtype of OCD and OCD patients
unresponsive to a serotonin-reuptake inhibitor alone may benefit from the addition of a
dopamine antagonist (Delgado et al, 1990).
b) Extended-release Formulation
1) In a 12-week, multicenter, randomized, double-blind, placebo-controlled study (n=253),
treatment with extended-release (ER) fluvoxamine maleate was safe and led to a statistically
significant and clinical relevant decrease in obsessive-compulsive disorder (OCD) severity in
adult patients. Patients meeting the DSM-IV criteria for OCD (mean duration, approximately 16
years), and with scores of 21 or higher on the Yale-Brown Obsessive Compulsive Scale (YBOCS) and 16 or lower on the 17-item Hamilton Rating Scale for Depression randomly
received either fluvoxamine ER (n=127; mean age, 38.1 years) or placebo (n=126; mean age,
36.7 years) orally once daily for 12 weeks. Fluvoxamine ER was initiated at a nightly dose of
100 milligrams (mg) and titrated in weekly 50-mg increments over 6 weeks to a target dose of
100 to 300 mg/day. The dose remained constant during the remaining 6 weeks of the study
(mean daily dose at endpoint, 271 mg). Patients were assessed every 2 weeks using the YBOCS (primary efficacy measure) and the Clinical Global Impressions-Severity of Illness (CGIS) and -Improvement (CGI-I) scales. At baseline, the Y-BOCS scores were 26.6 and 26.3 in
the fluvoxamine ER and placebo groups, respectively. A modified intent-to-treat (including
patients with at least 1 postbaseline efficacy measurement) analysis of Y-BOCS total score
revealed a mean +/- standard error (SE) decrease from baseline to week 12 of 8.5 +/- 0.7
(31.7% change) in the fluvoxamine ER group compared to 5.6 +/- 0.7 (21.2% change) in the
placebo group (F=10.48; df=1218; p=0.001). There were significant treatment differences in
favor of fluvoxamine ER group for both the obsession (39.6% change vs 24.4% change; p less
than 0.001) and compulsion (34.3% vs 24.8%; p=0.048) subtotals of the Y-BOCS. Notably,
treatment differences were evident at week 2 and were sustained throughout the 12-week
study. Among secondary efficacy measures, compared to placebo, significant improvements
occurred in fluvoxamine ER-treated patients for both the CGI-S (-1 +/- 0.1 vs -0.6 +/- 0.1;
p=0.002) and the CGI-I (endpoint, 2.7 +/- 0.1 (range, 1 to 5) vs 3.2 +/- 0.1 (range, 1-6); p less
than 0.001) scores. More patients discontinued treatment due to adverse events in the
fluvoxamine ER versus placebo group (19% vs 6%). The most common adverse events
occurring with fluvoxamine ER at a higher frequency than placebo included nausea (34% vs
13%), insomnia (35% vs 20%), somnolence (27% vs 11), asthenia (25% vs 8%), diarrhea
(18% vs 8%), and anorexia (13% vs 5%). Abnormal ejaculation and anorgasmia (8% and 5%,
respectively) only occurred in the fluvoxamine ER group, and decreased libido was also
reported more frequently in the fluvoxamine ER group (7% vs 3%) (Hollander et al, 2003).
d) Pediatric:
1) Fluvoxamine maleate was significantly more effective than placebo in children (8 years or older) and
adolescents with obsessive compulsive disorder (OCD). In this 10-week, double-blind study, 120
children with at least a 6-month history of OCD were randomized to receive fluvoxamine or placebo.
During the first 4 weeks, the dose was titrated to patient response; the dose at 4 weeks was continued
for the last 6 weeks of the study. Efficacy was assessed via the Children's Yale-Brown Obsessive
Compulsive Scale which showed significant improvement at weeks 1 to 4, 6, and 10. No serious
adverse effects were reported. Fluvoxamine was safe and effective in children with OCD (Riddle, 1996).
2) Fluvoxamine maleate was effective in decreasing depression and bulimic symptoms, but its impact
on impulsive, suicidal, and anorectic symptoms was less clear. The safety and efficacy of fluvoxamine
were evaluated in the treatment of adolescent patients with obsessive compulsive disorder (n=14) and
major depression (n=6). Patients were age 13 to 18 and were treated for 8 weeks in an open-label trial.
They were rated at 2-week intervals using Y-BOCS (Yale-Brown Obsessive Compulsive Scale) and
other rating scales. Fluvoxamine maleate was more effective in OCD patients than in depressed
patients, as evidenced by significant decreases in Y-BOCS scores. The most common side effects were
dermatitis, insomnia, hyperactivity, excitement, anxiety, tremor and nausea. The drug was discontinued
in 4 patients because of more severe side effects (delirium, hallucinations) (Apter et al, 1994).
4.5.A.15 Panic disorder
a) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
In uncontrolled or placebo-controlled studies, fluvoxamine was effective for treating panic disorder in
patients with and without depression (Spiegel et al, 1996; Black et al, 1993a).
c) Adult:
1) Fluvoxamine was effective for treating panic disorder complicated by depression. In an 8-week,
open-label, flexible-dose trial, fluvoxamine was administered to 17 patients. Thirteen patients had panic
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 130
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof131
of 160
Page 131
244
disorder with agoraphobia; 14 patients had an additional anxiety disorder; 15 patients had a major
depressive disorder; and 5 patients also had obsessive-compulsive disorder. Fluvoxamine was initiated
at 40 milligrams per day, increased to 100 milligrams on day 5 and to 150 milligrams on day 9. The
dose was increased at 50 milligram intervals each week until side effects occurred; the maximum dose
of 300 milligrams was reached; or panic attack and depression resolved. Fifteen patients completed the
study. One patient dropped out due to side effects and one for unknown reasons. The most common
adverse events were nausea, insomnia, anxiety/restlessness, headache, drowsiness and dry mouth. At
the study's end (at a mean fluvoxamine dose of 213 milligrams), there was a statistically significant
difference from baseline in the number of panic attacks, anticipatory anxiety, general anxiety,
depression and a self-rating of disability; however, fluvoxamine did NOT affect agoraphobia avoidance
(Spiegel et al, 1996).
2) Fluvoxamine was superior to cognitive therapy (CT) and placebo (PL) in the treatment of seventyfive outpatients with moderate-to-severe panic disorder. CT subjects also showed improvement but the
degree of improvement was not different from that of PL patients. Fluvoxamine also produced
improvement earlier than CT; at week 4, 57% of fluvoxamine patients were rated moderately improved
or better compared to 40% for the CT group and 22% for the PL group. At the same time point, 43% of
fluvoxamine patients were free of panic attacks compared with 25% of CT and 4% of PL patients (Black
et al, 1993a).
3) In a case report, fluvoxamine 150 milligrams/day for 6 weeks prevented panic attacks and
decreased obsessive-compulsive symptoms in a 36-year-old woman (Servant et al, 1988). The patient
had a 12-year history of recurrent panic attacks. The patient had most recently been treated with
imipramine 150 mg/day and lorazepam 2.5 mg/day without improvement.
4) In a placebo-controlled, double-blind study, fluvoxamine significantly reduced the number of panic
attacks compared to placebo. The severity of attacks was not affected by fluvoxamine. There was no
difference between drug and placebo until 6 weeks of treatment when placebo lost its effect on anxiety,
depressive mood, and disability (Hoehn-Saric, 1993).
4.5.A.16 Posttraumatic stress disorder
a) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
Open trials suggest that fluvoxamine may be useful for treating post-traumatic stress disorder (Escalona
et al, 2002; Davidson et al, 1998; Marmar et al, 1996).
c) Adult:
1) Some symptoms of combat-related post-traumatic stress disorder (PTSD) improved during treatment
with fluovoxamine; however, there was a high drop-out rate from the study due to side effects and lack
of perceived therapeutic benefit. Fifteen Vietnam combat veterans with no other psychiatric diagnosis
than PTSD and depression were treated with fluvoxamine, starting at a dose of 50 milligrams (mg) twice
daily and increasing to a maximum of 300 mg/day, in an open-label, 14- week study. The study was
preceded by a 30-day washout period. The mean daily dose of fluvoxamine at week 14 was 150 mg.
Only 8 patients completed 8 weeks of the study and 5 completed the entire study. In intent-to-treat
analysis, scores on intrusion and avoidance scales of the Clinician PTSD Scale (CAPS) showed
significant improvement (p less than 0.001), as did scores on the Hamilton Anxiety Scale (p less than
0.001). However, measures of depression showed no significant changes. Hyperarousal scores also
were unchanged. Gastrointestinal side effects and dizziness were the most common adverse effects
reported (Escalona et al, 2002).
2) In an open, 8-week trial, fluvoxamine resulted in symptom improvement in 64.2% of civilian patients
with post-traumatic stress disorder (PTSD). Fifteen patients with confirmed PTSD were treated with
fluvoxamine 50 milligrams (mg) daily with adjustment of dose to a maximum of 200 mg daily depending
on symptom improvement and side effects. Using assessment scales including the Structured Interview
for PTSD, Treatment-Outcome PTSD Scale, and the Duke Global Rating Scale for PTSD, the symptom
score improved by 40% to 50%; this difference was clinically and statistically significant. Five patients
left the trial early due to adverse effects (n=2) and administrative reasons (n=3); however, 14 of 15
patients were included in the efficacy analysis. Positive results of this and an earlier trial indicate that a
double-blind, placebo-controlled trial should be performed with fluvoxamine for PTSD (Davidson et al,
1998).
3) In an open-label trial, fluvoxamine improved stress-related symptoms in 10 Vietnam combat
veterans with post-traumatic stress disorder. The 12-week study consisted of a drug wash out and
DSM-IIIR diagnoses screening during weeks 0 to 2, followed by fluvoxamine 50 milligrams (mg) daily
starting at week 2. Fluvoxamine was increased weekly by 50 mg to a therapeutic dose; the (modal)
daily dose was 150 mg, (range 100 to 250 mg daily). Self-report and clinician ratings of stress-specific
and general psychiatric symptomatology improved significantly over the first 6 weeks and continued at
this level for the duration of the study. These included the intrusion, avoidance and hyperarousal
symptoms of PTSD. The comorbid features of depression and anxiety were also significantly affected;
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 131
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof132
of 160
Page 132
244
however, hostility was unaffected. The most commonly reported side effects were sedation, headache,
nausea, and insomnia (Marmar et al, 1996).
4.5.A.17 Premenstrual dysphoric disorder
a) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
With the exception of food cravings, symptoms associated with premenstrual syndrome were
significantly improved by the use of fluvoxamine in an open-label study (Freeman et al, 1996).
c) Adult:
1) With the exception of food cravings, symptoms associated with premenstrual syndrome were
significantly improved by the use of fluvoxamine (Freeman et al, 1996). In an open-label, pilot study,
fluvoxamine was examined for the treatment of premenstrual dysphoric disorder (PDD), commonly
referred to as PREMENSTRUAL SYNDROME. Twelve women who met the DSM-IV criteria for PDD
were treated with fluvoxamine for 2 menstrual cycles. Fluvoxamine was started at 50 milligrams per day
on day 1 of the menstrual cycle. At 4 weeks, the mean daily dose was 85 milligrams and at 8 weeks, all
women took 100 milligrams daily. Eight of the 10 women completing the study reported side effects.
Commonly reported side effects included insomnia, fatigue, dry mouth, nausea and loss of libido. Most
effects were transient and were only experienced early in the treatment. Improvement in the daily
symptom reports (DSR) was significant at both 4 and 8 weeks. Four factors, mood, function, pain and
physical changes made up the DSR. Seventeen individual items were contained within these 4 factors.
Further controlled studies are needed to substantiate these findings. It would also be helpful to
determine if fluvoxamine is needed on a daily basis throughout the menstrual cycle.
4.5.A.18 Prostatic pain
a) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
Fluvoxamine reduced pain and normalized urinary flow rates in patients with prostatodynia in a
randomized, double-blind, placebo-controlled study (n=42) (Turkington et al, 2002).
c) Adult:
1) Fluvoxamine treatment was more likely than placebo to reduce pain and normalize urinary flow rates
in patients with prostatodynia. In this randomized, double-blind, placebo-controlled study (n=42),
patients with at least a one-year history of perigenital pain without local or systemic infection and
without local inflammation were assigned to receive placebo or fluvoxamine for 8 weeks. Treatment
medication was initiated at 50 milligrams (mg) daily, then increased by 50 mg every 2 weeks, as needed
(median dose, 150 mg; range, 50-300 mg). Patients treated with fluvoxamine reported significant
improvements in pain as compared with placebo-treated patients (p=0.01). Significantly more patients in
the fluvoxamine group showed improvement in urinary flow rate as compared with the placebo group (7
of 8 vs 1 of 6, respectively; p=0.03). Larger studies are needed to address the efficacy of fluvoxamine
for all symptoms of prostatodynia and to identify the optimal dose (Turkington et al, 2002).
4.5.A.19 Repetitive self-excoriation
a) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class III
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
A response rate of 50% was seen in patients treated with fluvoxamine in an open-label study
(Arnold et al, 1999).
c) Adult:
1) In an open, 12-week study, patients with psychogenic excoriation improved during treatment with
fluvoxamine; however, 7 patients withdrew early due to adverse effects (n=4) or unrelated reasons.
Response defined as a 30% or greater decrease in the total score on the modified Yale-Brown
Obsessive Compulsive Scale (Y-BOCS) was achieved in 50% of enrolled patients. The modified YBOCS score was reduced from 17.9 at baseline to 10.9 at termination. Adverse effects were common
and included those normally expected with fluvoxamine. This study suggests that fluvoxamine may be
useful for psychogenic excoriation; however, controlled clinical trials are needed to confirm this (Arnold
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 132
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof133
of 160
Page 133
244
et al, 1999).
4.5.A.20 Severe major depression with psychotic features
See Drug Consult reference: PSYCHOTIC DEPRESSION - DRUG THERAPY
4.5.A.21 Social phobia
FDA Labeled Indication
a) Overview
FDA Approval: Adult, yes (extended-release formulation only); Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIa
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
Extended-release fluvoxamine maleate is indicated for social anxiety disorder, also known as social
phobia (Prod Info LUVOX(R) CR extended-release oral capsules, 2008).
In a randomized, double-blind, multicenter, placebo-controlled study (n=300), patients with
generalized social anxiety disorder (GSAD) who received fluvoxamine controlled-release (CR)
demonstrated a significantly greater reduction in the mean Liebowitz Social Anxiety Scale (LSAS)
total score from baseline compared with patients who received placebo (Westenberg et al, 2004);
there was a trend towards continued clinical benefit with fluvoxamine ER compared to placebo in a
12-week double-blind extension phase of this study (Stein et al, 2003).
c) Adult:
1) Fluvoxamine extended-release (ER) was an effective therapy in the treatment of patients with
generalized social anxiety disorder (GSAD). In a randomized, double-blind, placebo-controlled,
multicenter study, patients (n=300) with GSAD and a score of at least 60 on the Liebowitz Social
Anxiety Scale (LSAS) received fluvoxamine ER (initial, 100 milligrams (mg)/day, titrated weekly in 50
mg increments, as needed, to maximum of 300 mg/day; mean dose, 209 mg/day) for 12 weeks. A
significantly greater reduction in the mean LSAS total score was observed from baseline to endpoint in
the fluvoxamine ER group as compared with the placebo group (37% vs 28%, respectively; p=0.02).
The mean LSAS total score for patients in the fluvoxamine ER group was significantly more improved
as compared with placebo at weeks 4, 8, 10, and 12 (p less than 0.05, all values), but not at week 6
(p=0.066). Reductions on the fear and avoidance subscales of the LSAS were also significantly greater
for fluvoxamine ER-treated patients as compared with placebo-treated patients (p=0.015 and p=0.04,
respectively). Additionally, fluvoxamine ER was superior to placebo in three of four secondary measures
including the Clinical Global Impression Improvement (CGI-I) Scale, CGI-Severity (CGI-S) of Illness
Scale, and the Sheehan Disability Scale (SDS) (p=0.026, p=0.022, and p=0.036, respectively). Nausea
(47%), headache (35%), insomnia (32%), asthenia (28%), and somnolence (22%) were the most
commonly reported adverse events. Adverse effects related to sexual dysfunction were not significantly
different between treatment groups, however these effects included abnormal ejaculation, anorgasmia,
impotence, and decreased libido (Westenberg et al, 2004).
a) In a 12-week double-blind extension of the aforementioned study, there was a trend towards
continued clinical benefit with fluvoxamine ER (n=56) compared to placebo (n=53) among patients
with generalized social anxiety disorder. Patients completing the 12-week acute phase study and
achieving at least minimal improvement (ie, a CGI-I score of 3 or less) continued to receive study
medications as assigned in the acute phase; the mean fluvoxamine ER dose in the extension
phase was 181 milligrams/day. Notably, the extension phase was not powered to detect statistical
significance due to the small number of patients expected to continue into the extension study. At
the end of 24 weeks of treatment, the mean +/- standard error (SE) LSAS total scores continued to
decline in the fluvoxamine ER group compared to placebo (difference from week 12, -6.3 +/- 1.6 for
fluvoxamine ER versus (vs) -1.6 +/- 1.6 for placebo; p=0.109). Although not statistically significant,
greater improvements were seen in the fluvoxamine ER group compared to placebo for the
secondary measures of CGI-S and SDS scores during the 12-week extension. The percentage of
responders (ie, score of 1 or 2 on the CGI-I; 80% vs 74%; p=0.322) and remitters (ie, score of 1 on
the CGI-I; 38% vs 28%; p=0.318) was numerically higher in the fluvoxamine ER group than the
placebo group. During the extension phase, 9% (5/56) and 4% (2/53) of fluvoxamine ER- and
placebo-treated patients, respectively, discontinued treatment due to adverse events. Common
adverse events occurring more frequently than placebo included sweating (9% vs 4%), nausea (7%
vs 2%), and sexual dysfunction (16% vs 5%), with 7% of fluvoxamine ER-treated patients reporting
abnormal ejaculation (0% in the placebo group) (Stein et al, 2003).
2) Fluvoxamine was superior to placebo for treating social phobia. Patients diagnosed with DSM-IV
social anxiety disorder were randomly assigned to 12 weeks of double-blind treatment with placebo
(n=44) or fluvoxamine 50 milligrams daily (n=42) with titration at weekly intervals to a maximum dose of
300 milligrams daily. Response was defined by a score of 1 (very much improved) or 2 (much
improved) on the Clinical Global Impression scale (CGI). Of the patients (n=64) who completed the full
12 weeks of the study, 53.3% and 23.5% treated with fluvoxamine and placebo, respectively, were
considered responders on the CGI scale (p=0.01). In addition, evaluation using specialized social
phobia scales demonstrated significant improvement in the fluvoxamine versus placebo group (ie, Brief
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 133
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof134
of 160
Page 134
244
Social Phobia Scale, p less than 0.01; Social Phobia Inventory, p=0.02; Liebowitz Social Anxiety Scale
subscales for work and family life, p=0.006 and p=0.02). The mean fluvoxamine dose was 202
milligrams/day at study end. Treatment was withdrawn due to adverse effects in 25% and 9.1% of
patients treated with fluvoxamine and placebo, respectively; nausea and insomnia were the primary
adverse effects that led to treatment discontinuation. Treatment benefit was first observed at 6 weeks
and continued through week 12 of the study. Comparison of fluvoxamine with other accepted
treatments is needed (Stein et al, 1999).
3) Fluvoxamine was effective in a small group of patients who met DSM-III-R criteria for social phobia.
Fifteen patients were treated with fluvoxamine 50 milligrams (mg)/day with titration to 150 mg/day as
needed; treatment was continued for 6 weeks. Five patients discontinued treatment due to adverse
effects or difficulty traveling for appointments. Assessment scales including the Hamilton Rating for
Anxiety, Brief Social Phobia Scale, Marks-Sheehan Phobia Scale, Fear Questionnaire, and Sheehan
Patient Rated Anxiety Scale showed a significant reduction from baseline to week 7. Patients also
reported a reduction in anxiety associated with giving a speech at baseline and conclusion of the study.
This small, open study suggests that fluvoxamine is effective for social anxiety disorder (DeVane et al,
1999).
4.5.A.22 Stereotypy habit disorder
a) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
Three patients responded to fluvoxamine with complete cessation of stereotypic behavior in 1 patient
c) Adult:
1) Of 3 elderly women with stereotypic behavior, 2 almost completely stopped the behavior, and 1 had
a partial response to fluvoxamine (Trappler & Vinuela, 1997). Pretreatment assessment with the
Abnormal Involuntary Movement Scales (AIMS) yielded a score of 13 to 16. The first patient gnawed on
her fingers, clothing, and towels but stopped this behavior after receiving fluvoxamine 50 milligrams
(mg) daily for 4 weeks; the AIMS decreased to 1. Treatment was continued for 10 weeks; this patient
remained symptom-free 6 months after stopping fluvoxamine. The second patient had almost complete
resolution of chewing on her sweater and finger sucking 3 weeks after increasing fluvoxamine to 100
mg daily; her AIMS also decreased to 1. The third patient caused constant irritation and infection to her
left eyelid due to constantly wiping it with her sleeve. This behavior partially abated after treatment with
fluvoxamine 150 mg daily; the AIMS went from 16 to 7. Therapy was tolerated well by all patients who
ranged in age from 81 to 88 years. Since 2 patients maintained a response after treatment withdrawal,
this behavior was considered responsive to fluvoxamine and is likely related to a serotonergic
mechanism.
4.5.A.23 Trichotillomania
a) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
Fluvoxamine may have beneficial effects in patients with trichotillomania (Stanley et al, 1997).
c) Adult:
1) In a 12-week, open trial, fluvoxamine treatment resulted in some improvement in trichotillomania.
Twenty-one patients were treated with fluvoxamine 50 milligrams (mg) daily with dosage adjustment to
a maximum of 300 mg daily. Of the 21 patients treated, only 13 completed the entire 12 weeks of
treatment. When the data were analyzed including patients completing the study, few statistically
significant differences were found in symptoms on the assessment scales; however, when all patients
were included, significant differences were found in several symptoms on the assessment scales. One
possible explanation for this difference includes early treatment withdrawal in patients with a good
response; another possible reason is the assessment scales were NOT well validated for
trichotillomania. Since some symptomatic improvement occurred in both groups (completers and noncompleters), controlled clinical trials are needed to assess fluvoxamine treatment for trichotillomania
(Stanley et al, 1997).
4.5.A.24 Wernicke-Korsakoff syndrome
a) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class III
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 134
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof135
of 160
Page 135
244
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
b) Summary:
Results of studies have been mixed when fluvoxamine was used for treating alcoholic Korsakoff
syndrome. Available studies have included only a few patients; therefore, larger, well-controlled
studies may resolve the controversy (O'Carroll et al, 1994; Stapleton et al, 1988).
c) Adult:
1) Fluvoxamine 200 milligrams/day was ineffective in the treatment of alcoholic Korsakoff syndrome in
8 patients who were treated for 4 weeks in a double-blind, placebo-controlled, crossover trial.
Fluvoxamine had no cognitive-enhancing effect as measured by a detailed neuropsychological battery
on a weekly basis. There was significant impairment in verbal fluency. Two patients developed a major
depressive episode in the fluvoxamine group; within 3 days of fluvoxamine discontinuation, their mood
returned to normal (O'Carroll et al, 1994).
2) Fluvoxamine 100 to 200 milligrams/day improved episodic memory in 7 patients with alcohol
amnestic disorder (Korsakoff's psychosis) in a 4-week, double-blind, crossover design study. These
improvements were significantly correlated with reductions in cerebrospinal fluid 5-HIAA levels,
suggesting that facilitation of serotonergic neurotransmission may ameliorate the episodic memory
failure in patients with alcohol amnestic disorder (Martin, 1989).
3) Fluvoxamine produced a small but significant improvement in memory performance in 5 alcoholic
ORGANIC BRAIN SYNDROME patients during a double-blind, crossover study. Fluvoxamine 200
milligrams/day for 4 weeks was administered to all patients. Overall improvement in performance was
associated with higher levels of fluvoxamine and lower levels of 5-hydroxy-indole-acetic acid (5HIAA), a
metabolite of serotonin, in the cerebrospinal fluid (Stapleton et al, 1988).
4.6 Comparative Efficacy / Evaluation With Other Therapies
Amineptine
Amitriptyline
Clomipramine
Clovoxamine
Desipramine
Dothiepin
Fluoxetine
Flupenthixol
Imipramine
Lithium
Lorazepam
Maprotiline
Mianserin
Milnacipran
Oxaprotiline
Paroxetine
Sertraline
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 135
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof136
of 160
Page 136
244
4.6.A Amineptine
4.6.A.1 Bulimia nervosa
a) Fifteen women with bulimia nervosa were treated with a combined cognitive-behavioral, nutritional and
antidepressant therapy (either amineptine 300 milligrams (mg) per day or fluvoxamine 300 mg/day) for 4
months. The combination of psychotherapeutic and pharmacologic therapy showed rapid, good effects and
improvement was stable in most of the patients until the end of the observations. Prior to therapy, the
patients had high global Eating Disorders Inventory (EDI) scores; these did not change during fluvoxamine
therapy and decreased during amineptine administration in some patients (not statistically significant). No
statistically significant improvement (p=0.4) was found in depression or anxiety in the two groups. The
Bulimic Investigation Test Edinburgh (BITE) symptoms and gravity scores improved significantly (p=0.001)
in both groups and gravity was more significantly (p=0.05) improved with amineptine than fluvoxamine.
Optimum dosage and duration of treatment for this condition have not been determined. The data of this
study are preliminary and the results need to be validated in a larger population over a longer observation
period (Brambilla et al, 1995).
4.6.B Amitriptyline
Depression
Fibromyalgia
4.6.B.1 Depression
a) SUMMARY: In two clinical studies, amitriptyline and fluvoxamine were equally effective in treating
patients with depression (Gasperini et al, 1992; Remick et al, 1994). A greater percentage of the
amitriptyline group discontinued therapy due to side effects (Remick et al, 1994).
b) In a double-blind, randomized parallel study lasting seven weeks, fluvoxamine (mean dose 175 mg/day)
was compared to amitriptyline (mean dose 135 mg/day) in 33 outpatients with moderate degrees of
depression. There was no statistically significant difference between the two drugs as judged using the
Hamilton Rating Scale for Depression and the Clinical Global Impression Scale. The two drugs had a
comparable safety profile, although a greater percentage of the amitriptyline group discontinued therapy due
to side effects (Remick et al, 1994).
c) In another study, amitriptyline was compared to fluvoxamine in a double-blind trial of 56 patients with
major depressive disorders. The study lasted 6 weeks and doses of amitriptyline and fluvoxamine escalated
from 50 to 300 mg and 100 to 300 mg, respectively. Patients were divided into responders and nonresponders based on the Hamilton rating scale for depression and the Montgomery-Asberg depression
rating scale. Overall, the drugs were found equally effective, but there was some symptom specificity which
might guide the selection of one or the other drug in the clinical setting (Gasperini et al, 1992).
4.6.B.2 Fibromyalgia
a) Fluvoxamine was equally effective to amitriptyline in reducing pain associated with fibromyalgia. In an
open-label, uncontrolled study, 68 Japanese patients with fibromyalgia received either amitriptyline at a
mean dose of 20 milligrams (mg)/day or fluvoxamine at a mean dose of 25 mg/day for 4 weeks. Patients
evaluated pain relief by means of a visual analog scale and efficacy was defined as a decrease in pain by at
least 50%. At 4 weeks, 50% of patients in the amitriptyline group and 41% of patients in the fluvoxamine
group reported effective relief of pain (p=NS). Drowsiness was the most commonly reported adverse event
with amitriptyline treatment and nausea was most frequently reported with fluvoxamine. The authors
hypothesize that because the efficacy of amitriptyline for the treatment of fibromyalgia-related pain has been
established in previous, controlled trials and because fluvoxamine showed similar efficacy to amitriptyline in
this open-label study; fluvoxamine may be helpful for patients with fibromyalgia (Nishikai & Akiya).
4.6.C Clomipramine
Anxiety
Cataplexy
Depression
Obsessive-compulsive disorder
Panic disorder
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 136
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof137
of 160
Page 137
244
4.6.C.1 Anxiety
a) Fluvoxamine and clomipramine were comparable in reducing anxiety symptoms in patients with
agoraphobia with panic attacks (APA), generalized anxiety disorders (GAD), and obsessive-compulsive
disorders (OCD) as classified by DSM-III during a randomized, double-blind study (Westenberg et al, 1987).
Of the 50 patients in this study, 39 diagnosed with APA, 5 with GAD, and 6 with OCD. Patients were
randomly assigned to receive either clomipramine, up to 150 milligrams/day, or fluvoxamine, up to 100
milligrams/day, for the 6-week study. Both drugs demonstrated significant improvement in anxiety symptoms
after drug therapy when compared to pretreatment.
4.6.C.2 Cataplexy
a) Both fluvoxamine and clomipramine improved cataplexy, but not narcolepsy, in 18 patients with these
diseases during a cross-over study (Schachter & Parkes, 1980). It was not revealed if either the patients or
researchers were blinded to drug therapy. It should be noted that 15 of the 18 patients were receiving
clomipramine 25 to 100 milligrams/daily at the start of the trial, and may have been accustomed to the
adverse effects of clomipramine. Also, if the patients were not blinded to drug therapy, some patients may
have associated more adverse effects with a new drug, fluvoxamine. Patients were randomly allocated to
receive fluvoxamine or clomipramine for a 3-week interval. After a 1-week drug-free period, the patients
crossed over to the other drug. The daily dosing range for both drugs ranged from 25 to 200 milligrams/day.
All patients were clinically assessed by observers on 5 occasions. The observers' impression was that
fluvoxamine caused a moderate reduction in the frequency of attacks of cataplexy and sleep paralysis in
most subjects. Fluvoxamine abolished cataplexy in 4 patients and sleep paralysis in 2 patients; only 12 of
the 18 patients completed the fluvoxamine-treatment period. The observers felt that clomipramine was more
effective than fluvoxamine in preventing both cataplexy and sleep paralysis. Clomipramine abolished
cataplexy in 4 patients and sleep paralysis in 5 patients.
4.6.C.3 Depression
a) SUMMARY: Several double-blind, short-term studies have demonstrated fluvoxamine to be as effective
as clomipramine in the treatment of depression (De Wilde et al, 1983; Klok et al, 1981). Anticholinergic
adverse effects appear to be less common with fluvoxamine therapy.
b) Fluvoxamine and clomipramine were compared for antidepressant activity in a 6-week, randomized,
double-blind study of 43 outpatients with major depression (De Wilde et al, 1983). Oral fluvoxamine 100 to
300 milligrams or oral clomipramine 50 to 150 milligrams was administered once daily in the evening.
Assessments of the HAM-D (Hamilton Rating Scale for Depression) during the study and at the end failed to
demonstrate any significant differences in antidepressant activity between the 2 drugs. The incidence of
anticholinergic adverse effects were slightly more significant in the clomipramine-treated group.
c) Clomipramine and fluvoxamine appeared to be equally effective in the treatment of depression for 36
female inpatients during a 4-week, randomized, double-blind study (Klok et al, 1981). Patients were
randomized to receive either oral clomipramine or oral fluvoxamine 50 milligrams 3 times daily. Diazepam 10
to 30 mg/day for severe agitation and/or anxiety was the only other psychotropic agent administered.
Significant improvements in the Hamilton Rating Scale for Depression, the Clinical Global Impression, and
the Zung Self-Rating Depression scale were seen in both treatment groups. Anticholinergic adverse effects
appeared more frequently in the clomipramine-treated patients, while gastrointestinal effects were more
prevalent in the fluvoxamine group.
d) Fluvoxamine and clomipramine appeared to have similar clinical efficacy in the treatment of endogenous
depression for 30 unipolar and bipolar inpatients during a 4-week, randomized, double-blind study (De Wilde
et al, 1983). Both drugs were administered orally in doses of 150 to 300 milligrams/day in 3 divided doses.
At the end of the study, the fluvoxamine-treated patients demonstrated a 73% improvement on the Hamilton
Rating Scale for Depression, while the clomipramine-treated patients had a 62% improvement. In the bipolar
patients, 3 of 4 on fluvoxamine responded, while only 1 of 5 on clomipramine demonstrated a good
response on the CGI Global Change Scale. Overall, the differences in efficacy between the 2 drugs were not
statistically significant. Adverse anticholinergic effects were significantly more prevalent in the clomipraminetreated group.
e) Both clomipramine and fluvoxamine produced significant improvements on the Hamilton Rating Scale for
Depression (HAM-D) in 32 patients with mixed depression during a 4-week, randomized, double-blind study
(Dick & Ferrero, 1983). The average daily dosage was 130 milligrams and 132.8 milligrams for fluvoxamine
and clomipramine, respectively. The mean percentage improvement on the HAM-D for the fluvoxaminetreated patients was 63.8%, and for the clomipramine-treated patients it was 66.3%.
4.6.C.4 Obsessive-compulsive disorder
a) Fluvoxamine (150 to 125 milligrams/day) and clomipramine (100 to 250 milligrams/day were equally
effective in the treatment (10 weeks) of 66 outpatients with obsessive compulsive disorder. Both treatments
were well-tolerated. Fluvoxamine produced fewer anticholinergic adverse effects and caused less sexual
dysfunction than clomipramine, but caused more headache and insomnia (Freeman et al, 1994). under
OBSESSIVE COMPULSIVE DISORDER add:
b) In a randomized, double-blind study of 26 patients with obsessive compulsive disorder without comorbid
diseases, fluvoxamine and clomipramine, each titrated from an initial dose of 50 milligrams (mg) in the
evening up to a maximum of 300 mg daily within two weeks, were equally effective (38% improvement over
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 137
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof138
of 160
Page 138
244
baseline with fluvoxamine versus 40% for clomipramine). Efficacy was assessed according to the YaleBrown Obsessive Compulsive Scale and Clinical Global Impression Scale. Fluvoxamine was better
tolerated, with less anticholinergic adverse effects while clomipramine had a quicker onset of action. Further
studies are needed to demonstrate a time-related effect that might differentiate these drugs (Milanfranchi et
al, 1997).
4.6.C.5 Panic disorder
a) Clomipramine (10 milligrams (mg) for three days and 20 mg for four days) and fluvoxamine (50 mg/day
for seven days) were both effective in decreasing the hypersensitivity to 35% carbon dioxide, supporting the
serotonergic effect of these drugs to decrease panic attacks through modification of carbon dioxide
sensitivity. Thirty-nine panic disorder patients were enrolled in a double-blind, randomized, placebocontrolled study, where each patient was given the 35% carbon dioxide challenge on days 0, 3, and 7.
Patients on clomipramine and fluvoxamine showed significant reduction in sensitivity over placebo after
seven days as seen by the percent change on a visual analogue for anxiety scale (p=0.027) (Perna et al,
1997).
4.6.D Clovoxamine
1) Efficacy
a) SUMMARY: Clovoxamine induces only minor electroencephalographic changes in healthy subjects;
whereas, changes produced by fluvoxamine more closely resemble those of imipramine, including an
increase of slow activity. Clovoxamine appears less sedating than fluvoxamine, and may possess mild
alerting effects.
b) In computerized electroencephalographic studies involving healthy subjects (Saletu et al, 1980), oral
clovoxamine 50 to 125 mg was primarily associated with an increase in very fast beta-activity (predominant
6 hours postdose), suggesting an activating effect of the drug. Although an increase in fast beta-activity was
also observed with fluvoxamine 75 mg, this agent also produced a concomitant increase of slow activity and
a decrease of alpha-activity. Imipramine 75 mg produced the most marked electroencephalographic
changes, characterized by a concomitant increase of slow and fast activities and a decrease of alphaactivity. Augmentation of slow activity was, however, less with fluvoxamine than imipramine, suggesting less
sedative properties of the former. Overall, pharmacodynamic data based on both electroencephalographic
and psychometric parameters indicated that imipramine 75 mg produced the most central nervous system
changes, followed by fluvoxamine 75 mg, clovoxamine 125 mg, clovoxamine 75 mg, and clovoxamine 50
mg. Peak effects occurred 4 to 6 hours after clovoxamine and fluvoxamine, compared to 2 to 4 hours
following imipramine. Adverse effects were minimal with clovoxamine, with euphoria occurring in a few
subjects; in contrast, tiredness was common after fluvoxamine (50% of subjects) and imipramine (80%).
c) The results of a further placebo-controlled study in healthy volunteers also suggested a lower propensity
of clovoxamine to induce sedation in comparison with fluvoxamine. In doses of 50 mg twice daily (8 am and
6 pm), fluvoxamine was associated with changes suggestive of enhanced nighttime sedation; fluvoxaminetreated were significantly less refreshed upon awakening and had greater difficulty in achieving morning
alertness compared to placebo, and there were trends toward fewer nocturnal awakenings and shorter sleep
latency in the fluvoxamine group. In contrast, these effects were not observed clovoxamine 150 mg daily
(100 mg at 8 am and 50 mg at 6 pm); depth of sleep was reduced significantly with clovoxamine compared
to placebo (Ochs et al, 1989).
4.6.E Desipramine
4.6.E.1 Depression
a) The efficacy of fluvoxamine was compared to that of desipramine in a multicenter, double-blind, placebocontrolled six-week flexible dose trial of 90 outpatients with major depressive disorder. Dosage range for
each active medication was 100 to 300 milligrams/d. The Montgomery-Asberg Depression Rating Scale, the
Hamilton Rating Scale for Depression, and the Clinical Global Impression Scale were used to assess
response. There was no significant difference in efficacy among the three treatments until week six, when
both active drug groups continued to improve while the placebo group remained at the same level of
depression. The authors concluded that 6 weeks was too short a time to identify the differences between
active drug and placebo in the patient population (Roth et al, 1990).
b) An immediate increase in pain threshold (polysynaptic R-III reflex and subjective pain rating to electric
shock) was seen in a single-dose, placebo-controlled study comparing desipramine, fluvoxamine, and
moclobemide in healthy volunteers (n=10) (Coquoz et al, 1993).
4.6.F Dothiepin
4.6.F.1 Depression
a) Fluvoxamine and dothiepin were comparable in reducing symptoms of depression in 73 patients during a
6-week, double-blind study (Mullin et al, 1988). The patients were randomized to receive initial starting
doses of either fluvoxamine 100 milligrams or dothiepin 75 milligrams daily. The doses were increased
gradually, as tolerated, to a maximum of fluvoxamine 300 milligrams or dothiepin 225 milligrams/day. At the
conclusion of the study, both drugs demonstrated efficacy in treating depression as measured by the
Hamilton Depression Rating Scale (HAMD), Clinical Global Impression, and Clinical Global Improvement
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 138
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof139
of 160
Page 139
244
scales. There were no significant differences in efficacy between the 2 drugs. Dothiepin was associated with
more anticholinergic adverse effects, while fluvoxamine was associated with more nausea and vomiting.
b) Fluvoxamine (25 to 200 mg/d) was equivalent to dothiepin (25 to 200 mg/d) in efficacy in 52 elderly
inpatients with major depressive disorder. Patients were treated for 6 weeks with weekly assessments for
therapeutic response and presence of adverse effects. The mean dosage during the last 2 weeks of the
study was 157 mg/d for fluvoxamine and 159 mg/d for dothiepin. Sixty-three percent of fluvoxamine patients
and 60% of dothiepin patients showed marked improvement at six weeks (Rahman et al, 1991).
4.6.G Fluoxetine
4.6.G.1 Depression
a) In a randomized, double-blind study (n=100), fluvoxamine and fluoxetine demonstrated comparable
efficacy and side effects in out-patients with major depression. After randomization, patients were treated
initially with fluvoxamine 50 milligrams (mg) daily adjusted to a maximum of 150 mg daily or fluoxetine 20 mg
daily adjusted to a maximum of 80 mg daily. Throughout the study, significant differences in efficacy were
NOT detected on several depression scales including the Hamilton depression scale and clinical global
impressions scale. Adverse effects were common with both drugs but the severity was mild in the majority of
patients. Even though this study included 100 patients, it may NOT have detected subtle differences
between the 2 treatments (Rapaport et al, 1996).
4.6.H Flupenthixol
4.6.H.1 Depression
a) Flupenthixol was as effective as fluvoxamine in the treatment of depression, and had a more favorable
adverse effect profile (Hamilton et al, 1989). In a multicenter trial, 72 patients with depression were
randomized to receive either flupenthixol 1 milligram/day (n=36) or fluvoxamine 100 milligram/day (n=36) for
4 weeks. Patients were evaluated objectively on days 1, 8, 15, and 29 using the Hamilton Depression Rating
Scale, the Clinical Global Impressions Scale, and a self-assessment analog scale. At the end of the first
week, the dose was doubled if response was judged to be insufficient. While both drugs were shown to be
effective, mean improvement scores were higher at all evaluation times as measured by any of the 3
parameters in the group receiving flupenthixol. At the end of the first week, 89% of the flupenthixol group
showed at least minimal improvement, compared with 75% of the fluvoxamine group. At the end of the
study, all patients receiving flupenthixol had responded to treatment, compared with 83% of the fluvoxamine
group. Four patients taking fluvoxamine were withdrawn due to adverse effects, but no patients receiving
flupenthixol were withdrawn.
4.6.I Imipramine
4.6.I.1 Depression
a) SUMMARY: Fluvoxamine and imipramine appear to be equally efficacious in the treatment of depression
(Lapierre et al, 1987; Guelfi et al, 1983; Guy et al, 1984; Itil et al, 1983); (March, 1990)(Lydiard et al, 1989).
b) Fluvoxamine demonstrated a trend toward superiority over imipramine in treating 63 patients with major
depression during a 4- to 6-week, randomized, placebo-controlled, double-blind study (Lapierre et al, 1987).
All drugs were started at 50 milligrams/day, and were gradually increased to a maximum of 300 mg/day. The
mean daily dose of fluvoxamine at the the end of the study was 207 mg, and 192 mg for imipramine. At the
end of the study, the total Hamilton Rating Scale for Depression (HAM-D) score had decreased by 75%,
55%, and 6% in the fluvoxamine-, imipramine-, and placebo-treated groups, respectively. At the end of the
study there were 8, 3, and 1 responders from the fluvoxamine, imipramine, and placebo groups,
respectively. Only 1 patient in each active treatment group withdrew from the study because of adverse
effects.
c) Fluvoxamine was comparable to imipramine in antidepressant activity during a 4-week, double-blind,
multicenter study of 151 patients (Guelfi et al, 1983). Drug therapy was administered in twice daily dosing in
the range of 100 to 300 milligrams daily for fluvoxamine and 50 to 200 milligrams daily for imipramine. At the
end of the study there was a mean improvement in the Hamilton Rating Scale for Depression (HAM-D) of
67.2% in the fluvoxamine-treated group and a 62.1% improvement in the imipramine-treated group. A similar
improvement was detected with both drugs on the Clinical Global Impression Scale. At the end of the study,
the mean daily dose of fluvoxamine was 221 mg and 112 mg for imipramine. A total of 37 patients withdrew
from the study prematurely; 19 on fluvoxamine and 18 on imipramine. The reasons for early withdrawal
appeared to be similar between both drugs.
d) Fluvoxamine and imipramine were comparable in efficacy for the treatment of depression in 36 patients
diagnosed with unipolar or bipolar depression during a 4- to 6-week, randomized, double-blind study (Guy et
al, 1984). Both medications were administered at bedtime with a maximal dosage range between 150 to 225
milligrams/day. In the unipolar depressed fluvoxamine-treated patients, 92% were judged "improved" at the
end of the study compared to 81% of the imipramine group. However, the imipramine-treated group
appeared to have a higher percent of patients rated as "much" or "very much" improved, 75% compared to
54% of the fluvoxamine group.
e) A double-blind comparative study of fluvoxamine and imipramine was carried out in 20 outpatients with
depressive disorder. Patients received randomly-assigned medication over a 4-week period in a dosage
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 139
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof140
of 160
Page 140
244
range of 50 of 300 mg given in 2 divided doses. There was a significant symptom severity reduction in both
groups at the end of 4 weeks, and fluvoxamine was more effective than imipramine in reducing suicidal
ideas and anxiety/somatic symptoms. Anticholinergic-type adverse reactions predominated for imipramine
and gastrointestinal effects for fluvoxamine (Gonella et al, 1990).
f) In a 6-week, double-blind, placebo-controlled, variable-dose study assessing the comparative
antidepressant efficacy of fluvoxamine (FLU), imipramine (IMI), and placebo (PBO), 45 patients with major
depressive disorder were evaluated for response and side effects. Dosage ranged between 100 to 300
milligrams/day for active medications. No statistically significant differences between either the FLU (N=17)
and PBO or the FLU and IMI groups were found. Side effects were present in all three groups: IMI(N=18):
constipation (83%), dry mouth (55%), and sweating, dizziness, and nausea, all 39%. FLU(N=18): diarrhea,
headache, dry mouth, all 41%, nausea (35%), and flatus (29%). PBO(N=18): pruritus (29%, nausea (23%),
headache (18%), asthenia and somnolence, both 12%. This study revealed a high placebo response, with a
50% improvement at week 6. Thus, it is difficult to show differences from active medication unless the study
is carried out for a longer time. In addition, the numbers of patients are too small to detect a true difference.
Second, patients seemed to either respond or not respond to FLU, while the response to IMI appeared to be
more graded. This may reflect a subgroup of depressed patients that have a serotonin-deficient type of
depression (Lydiard et al, 1989).
g) Other double-blind, placebo-controlled studies comparing imipramine and fluvoxamine have only
demonstrated slightly more improvement in depression with either drug when compared with placebo
(Dominguez et al, 1985; Norton et al, 1984).
4.6.I.2 Adverse Effects
a) SUMMARY: Fluvoxamine produces less cardiovascular and anticholinergic adverse effects than
imipramine; however, nausea and vomiting are more common with fluvoxamine therapy (Benfield & Ward,
1986a; Roos, 1983; Saletu et al, 1980a; Laird et al, 1993).
b) Adverse effects data was pooled from the results of 10 double-blind, placebo-controlled trials comparing
fluvoxamine (n=222) with imipramine (n=221) (Benfield & Ward, 1986a). Anticholinergic effects such as dry
mouth, dizziness/syncope, sweating, and abnormal accommodation were much more prevalent in patients
receiving imipramine. Nausea/vomiting was the only adverse effect to be much more prevalent in the
fluvoxamine-treated patients.
c) The cardiac effects of tricyclic antidepressants were compared with fluvoxamine. The major cardiac
adverse effects observed with tricyclic antidepressants include postural hypotension, heart rate increase,
and slight prolongation of the intraventricular conduction time and QT interval. The only cardiac effect
observed with fluvoxamine was a statistically, but not clinically, significant slowing of heart rate (Roos,
1983).
d) Fluvoxamine produced less psychomotor impairment than imipramine. Fluvoxamine was superior to
imipramine 75 milligrams in regards to concentration, reaction time, mood, psychomotor activity, and
affectivity. Following the administration of fluvoxamine 75 milligrams to 10 healthy volunteers, psychometric
tests demonstrated a tendency towards an improvement in psychomotor activity, concentration, attention,
after-effect, and mood and a significant increase in critical flicker fusion frequency when compared to
placebo (Saletu et al, 1980a).
4.6.J Lithium
4.6.J.1 Depression
a) The rate of recurrence of unipolar depressive episodes was lower for fluvoxamine 200 milligrams (mg)
per day than lithium salts 600 to 900 mg/day in a randomized study of 64 unipolar patients. Follow-up
continued for 24 months (Franchini et al, 1994). Further follow-up at 36 months showed no additional
recurrences of depression in either the fluvoxamine or the lithium group (Franchini et al, 1996). Due to
methodological limitations, further studies are needed.
4.6.K Lorazepam
4.6.K.1 Depression
a) Fluvoxamine (50 to 300 mg/d) was compared with lorazepam (1 to 6 mg/d) in a multi-center, doubleblind, parallel group study in 112 general practice patients with mixed anxiety and depression. Response
was assessed over a 6-week period using the Montgomery-Asberg Depression Rating Scale (MADRS) and
the Clinical Anxiety Scale (CAS). There were no significant differences between treatments at any point
except in an elderly subgroup where anxiety improved more rapidly with lorazepam. There were significant
improvements in MADRS and CAS, and global ratings compared with baseline at all subsequent
assessments. Lorazepam produced more sedation while fluvoxamine produced more nausea and vomiting
(Laws et al, 1990).
4.6.L Maprotiline
4.6.L.1 Schizophrenia
a) Fluvoxamine was more effective than maprotiline for improving negative symptoms associated with
schizophrenia. Patients entered in this study had schizophrenia of at least 2 years duration and received
more than 1 antipsychotic with anticholinergics (stable dose maintained during study). Patients (n=38) were
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 140
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof141
of 160
Page 141
244
randomly assigned to fluvoxamine or maprotiline 50 milligrams (mg) daily which was increased to 100 mg
during the remaining 5 weeks of the study. Thirteen patients left the study within 2 weeks due to personal
reasons, side effects, or worsening symptoms; these patients were NOT included in the efficacy analysis.
The total score for the Scale for the Assessment of Negative Symptoms was significantly (p=0.045) lower in
the fluvoxamine (65.6 to 57.1) versus maprotiline (80.3 to 78) group; similar results were obtained for the
Brief Psychiatric Rating Scale for negative factors. Five (38.5%) patients in the fluvoxamine group were
responders (defined by 20% improvement in total SANS score) versus none in the maprotiline group. The
authors suggest that the serotonergic versus the antidepressant effect of fluvoxamine are responsible for the
change in negative symptoms. Further study is needed since the sample size was small, and many patients
left the study (Silver & Shmugliakov, 1998).
4.6.M Mianserin
4.6.M.1 Depression
a) Both fluvoxamine and mianserin are effective for the treatment of depressive illness (Perez & Ashford,
1990). Efficacy and CNS effects of fluvoxamine were compared with those of mianserin in depressed
outpatients in a 6-week double-blind trial. The study included active treatment with 100 to 300 milligrams/d
of fluvoxamine or 60 to 180 milligrams/d of mianserin. Data from 63 patients (30 fluvoxamine) showed
comparable efficacy at the end of 6 weeks. MADRS scores (Montgomery-Asburg Depression Rating Scale)
improved 65.6% with fluvoxamine and 60.8% with mianserin with no significant differences between
treatments at any assessment. Mianserin produced more sedation during the first week of treatment but this
difference resolved for the remainder of the study.
b) Fluvoxamine 50 to 200 milligrams and mianserin 20 to 80 milligrams/d were equivalent in efficacy and
tolerability in a study of 57 elderly patients with major depressive episode. Seven of 25 fluvoxamine patients
and 4 of 25 mianserin patients had to leave the study because of intolerable side effects (Phanjoo et al,
1991).
4.6.N Milnacipran
4.6.N.1 Depression
a) Although there was no significant difference in efficacy between groups of patients treated with
fluvoxamine or milnacipran when viewed overall, among the subset of severely depressed patients,
significantly more who were treated with milnacipran responded to treatment (50% or greater improvement
in Hamilton Depression Rating Scale (HDRS) score) than who were treated with fluvoxamine. The groups
comprised patients who had been treated with milnacipran (maximum dose 15 milligrams (mg) per day) for
at least 22 months (n=102) or with fluvoxamine (maximum dose 250 mg/day) for the same period (n=90).
Overall, 53% of milnacipran-treated patients and 47% of fluvoxamine-treated patients responded to
treatment. Among patients with an initial HDRS score of 19 or greater, 69% of those treated with milnacipran
and 46% of those treated with fluvoxamine responded (p=0.046). Scores showing improvement in insomnia
and agitation significantly favored milnacipran. There were no significant differences between groups for
individual or total adverse events. However, urological adverse events occurred more frequently in the
milnacipran group and gastrointestinal symptoms in the fluvoxamine group. Palpitations occurred only in the
milnacipran group (3%) (Fukuchi & Kanemoto, 2002).
b) Several comparative trials (mainly unpublished) have indicated no significant difference in efficacy
between milnacipran 50 to 150 mg twice daily and fluvoxamine 100 mg twice daily or fluoxetine 20 mg once
daily in major depression (Guelfi et al, 1998; Anon, 1997). One study reported the superiority of fluoxetine 20
mg once daily (statistically significant for most parameters) over milnacipran 100 mg once daily in major
depressive outpatients (Ansseau et al, 1994); however, this study suffered from methodological problems,
the most significant being once-daily dosing of milnacipran, which may not achieve therapeutic levels.
c) Meta-analyses of studies comparing milnacipran and fluoxetine/fluvoxamine have been performed by the
manufacturer; greater improvements (eg, Hamilton, Montgomery-Asberg) were described for milnacipran,
which were usually statistically significant (Lopez-Ibor et al, 1996; Anon, 1997; Elwood, 1997). However,
only a few trials were selected for analysis, and not all patients in these trials were evaluated; the superiority
of milnacipran was demonstrated only after results were subjected to multiple reanalysis (Anon, 1997).
d) Comparisons with other similar agents (eg, sertraline) are lacking.
4.6.O Oxaprotiline
4.6.O.1 Depression
a) Oxaprotiline appeared to be more efficacious than fluvoxamine in 71 depressed patients resistant to prior
tricyclic antidepressants during a randomized, double-blind, partial crossover study (Nolen et al, 1988).
Patients were randomized to receive either fluvoxamine or oxaprotiline at a starting dose of 50 mg BID,
which was gradually increased to a maximum of 150 mg BID as tolerated. The mean daily doses of
oxaprotiline and fluvoxamine at the end of 4 weeks were 260 mg and 288 mg, respectively. Only 9 of 33
(27%) patients receiving oxaprotiline demonstrated a response, while none of the fluvoxamine-treated
patients responded. During the second treatment phase, 55 patients were crossed over to the other drug.
The mean daily doses of oxaprotiline and fluvoxamine at the end of the second phase were 267 mg and 286
mg, respectively. Of the 31 patients completing at least 2 weeks of oxaprotiline therapy, 12 (38%)
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 141
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
Filed 03/24/2010
Pageof142
of 160
Page 142
244
responded; however, 6 (19%) relapsed within 6 months for a long-term response rate of only 19%. Of the 21
patients completing at least 2 weeks of fluvoxamine therapy, 2 patients (9%) responded with lasting effects.
4.6.P Paroxetine
4.6.P.1 Depression
a) Fluvoxamine and paroxetine produced similar improvements in depressive symptoms in patients with an
initial or recurrent episode of major depression. Adverse effects occurred in 100% and 97% of patients
treated with paroxetine and fluvoxamine, respectively. Fluvoxamine was associated with a higher incidence
of asthenia, dry mouth, somnolence, and insomnia; whereas, paroxetine caused a higher incidence of
headache, nausea, diarrhea, sweating, abnormal dreams, and sexual dysfunction. In this 7-week,
randomized, double-blind study, 58 patients were assigned to receive fluvoxamine 50 milligrams(mg)/day or
paroxetine 20 mg/day initially; the protocol allowed for dosage titration to fluvoxamine 150 mg/day or
paroxetine 50 mg/day. An additional 10 fluvoxamine- and 8 paroxetine-treated patients dropped out of the
study for various reasons, but all of the patients were included in the intent-to-treat efficacy analysis. Due to
the small sample size of this study, only large differences between treatments would be detectable;
therefore, larger studies are needed to detect differences in treatment effects between these drugs (Kiev &
Feiger, 1997).
b) The pharmacology, pharmacokinetics, adverse effects, drug interactions, efficacy, and dosage and
administration of fluvoxamine (FVX), sertraline (SRT) and paroxetine (PRX) were compared in a
comprehensive review (Grimsley & Jann, 1992). All three agents have large volumes of distribution and are
highly protein-bound. In contrast to fluoxetine, FVX, SRT, and PRX all have shorter elimination half-lives
(approximately 24 hours) and are metabolized to clinically-inactive compounds. Nausea was the most
commonly reported adverse effect for all three agents. Other reported adverse effects include sedation,
headache, dry mouth, insomnia, sexual dysfucntion, and constipation. FVX has been found to be superior to
placebo and equivalent to imipramine, clomipramine, desipramine, mianserin, and maprotiline in the
treatment of depression and both FVX and SRT have been shown to be superior to placebo in the treatment
of obsessive-compulsive disorder (OCD). PRX has been found to be superior to placebo and equivalent to
amitriptyline, imipramine, clomipramine, and doxepin in the treatment of depression while SRT has been
found to be superior to placebo and equivalent to amitriptyline. Clinical experience has demonstrated all
three drugs to be effective in the treatment of depression. They may be especially useful in elderly patients,
in those who cannot tolerate alternate treatments, and in those who do not respond to adequate trials of
other antidepressant therapies.
4.6.Q Sertraline
4.6.Q.1 Depression
a) In a small study (n=64), the incidence of recurrent depression was similar between patients treated
prophylactically with sertraline and fluvoxamine. Sixty-four patients entered the study and received either
sertraline 100 milligrams(mg)/day or fluvoxamine 200 mg/day for 2 years; increases in dose were allowed if
depression recurred. During the study period, 7 sertraline-treated and 6 fluvoxamine-treated patients had a
new episode of depression (p=0.88). Adverse effects were minor and transient for both treatments. Results
of this study suggest that sertraline and fluvoxamine were effective for preventing recurrent depression
episodes, but are limited by the absence of a placebo control group(Franchini et al, 1997).
b) The pharmacology, pharmacokinetics, adverse effects, drug interactions, efficacy, and dosage of
fluvoxamine (FVX), sertraline (SRT) and paroxetine (PRX) were compared in a comprehensive review
(Grimsley & Jann, 1992a). All three agents have large volumes of distribution and are highly protein-bound.
In comparison to fluoxetine, FVX, SRT, and PRX all have shorter elimination half-lives (approximately 24
hours) and are metabolized to clinically-inactive compounds. These agents, therefore, are less likely than
fluoxetine to interact with other drugs. Nausea was the most commonly reported adverse effect for all three
agents. Other reported adverse effects include sedation, headache, dry mouth, insomnia, sexual
dysfunction, and constipation. FVX has been found to be superior to placebo and equivalent to imipramine,
clomipramine, desipramine, mianserin, and maprotiline in the treatment of depression and both FVX and
SRT have been shown to be superior to placebo in the treatment of obsessive-compulsive disorder (OCD).
PRX has been found to be superior to placebo and equivalent to amitriptyline, imipramine, clomipramine,
and doxepin in the treatment of depression while SRT has been found to be superior to placebo and
equivalent to amitriptyline. Clinical experience has demonstrated all three drugs to be effective in the
treatment of depression. They may be especially useful in elderly patients, in those who cannot tolerate
alternate treatments, and in those who do not respond to adequate trials of other antidepressant therapies.
6.0 References
1.
2.
3.
4.
Ahman S: Hydralazine and male impotence. Chest 1980; 78:2.
Aizenberg D, Zemishlany Z, & Weizman A: Cyproheptadine treatment of sexual dysfunction induced by serotonin
reuptake inhibitors. Clin Neuropharmacol 1995; 18(4):320-324.
Alderman CP & Frith PA: Fluvoxamine-methadone interaction. Aust N Z J Psychiatry 1999; 33:99-101.
Aldrige SA: Drug-induced sexual dysfunction. Clin Pharm 1982; 1:141.
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 142
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
Filed 03/24/2010
Pageof143
of 160
Page 143
244
Amery A, Verhiest W, Croonenberghs J, et al: Double-blind crossover study of a new vasodilator-prazosin - in the
treatment of mild hypertension. Excerpta Medica International Congress Series 1974; 331:100.
Amsden GW & Georgian F: Orthostatic hypotension induced by sertraline withdrawal. Pharmacotherapy 1996; 16
(4):684-686.
Anderson KE, Bloomer JR, Bonkovsky HL, et al: Recommendations for the diagnosis and treatment of the acute
porphyrias. Ann Intern Med 2005; 142(6):439-450.
Anon: American academy of pediatrics committee on drugs: transfer of drugs and other chemicals into human
milk. Pediatrics 2001; 108(3):776-789.
Anon: Drugs that cause sexual dysfunction. Med Lett Drug Ther 1983; 25:73.
Anon: Endocrine basis for sexual dysfunction in men. Br Med J 1978; 4:1516.
Anon: FDA public health advisory: worsening depression and suicidality in patients being treated with
antidepressant medications. US Food and Drug Administration. Rockville, MD. 2004. Available from URL:
http://www.fda.gov.cder/drug/antidepressants/antidepressantpja.htm.
Anon: Labeling change request letter for antidepressant medications (letter). US Food and Drug Administration.
Washington, DC, USA. 2004a. Available from URL:
http://www.fda.gov.cder/drug/antidepressants/ssrilabelchange.htm. As accessed 12/01/2004.
Anon: Milnacipran: tricyclics remain first-line antidepressants. Rev Prescr 1997; 17:791-795.
Anon: Priapism with trazodone (Desyrel). Med Lett Drug Ther 1984; 26:35.
Anon: Veterans administration cooperative study group on antihypertensive agents. Comparison of propranolol
and hydrochlorothiazide for the initial treatment of hypertension. JAMA 1982; 248:2004.
Anon: Veterans administration cooperative study group on antihypertensive agents. Multiclinic controlled trial of
betanidine and guanethidine in severe hypertension. Circulation 1977; 55:519.
Ansseau M, Papart P, Troisfontaines B, et al: Controlled comparison of milnacipran and fluoxetine in major
depression. Psychopharmacology 1994; 114:131-137.
Apter A, Ratzoni G, King RA, et al: Fluvoxamine open-lable treatment of adolescent in patients with obsessivecompulsive disorder or depression. J Am Acad Child Adolesc Psychiatr 1994; 33:342-348.
Arlander E, Ekstrom G, Alm C, et al: Metabolism of ropivacaine in humans is mediated by CYP1A2 and to a minor
extent by CYP3A4: an interaction study with fluvoxamine and ketoconazole as in vivo inhibitors. Clin Pharmacol
Ther 1998; 64:484-491.
Arnatt S & Nutt D: Successful treatment of fluvoxamine-induced anorgasmia by cyproheptadine. Br J Psychiatry
1994a; 164:838-839.
Arnatt S & Nutt D: Successful treatment of fluvoxamine-induced anorgasmia by cyproheptadine. Brit J Psychiatry
1994; 164:838-839.
Arnold LM, Mutasim DF, Dwight MM, et al: An open clinical trial of fluvoxamine treatment of psychogenic
excoriation. J Clin Psychopharmacol 1999; 19(1):15-18.
Ashton AK & Rosen RC: Bupropion as an antidote for serotonin reuptake inhibitor-induced sexual dysfunction. J
Clin Psychiatry 1998; 59(3):112-115.
Australian Drug Evaluation Committee: Prescribing medicines in pregnancy: An Australian categorisation of risk of
drug use in pregnancy. Therapeutic Goods Administration. Australian Capital Territory, Australia. 1999. Available
from URL: http://www.tga.gov.au/docs/html/medpreg.htm.
Barbanel DM, Yusufi B, O'Shea D, et al: Mania in a patient receiving testosterone replacement post-orchidectomy
taking St. John's Wort and sertraline. J Psychopharmacol 2000; 14:84-86.
Barbanel DM, Yusufi B, O'Shea D, et al: Mania in a patient receiving testosterone replacement post-orchidectomy
taking St. John's Wort and sertraline. J Psychopharmacol 2000a; 14:84-86.
Barksdale JD & Gardner SF: The impact of first-line antihypertensive drugs on erectile dysfunction.
Pharmacotherapy 1999; 19(5):573-581.
Barr LC, Goodman WK, & Price LH: Physical symptoms associated with paroxetine discontinuation (letter). Am J
Psychiatry 1994; 151:289.
Bauer GE, Hull R, Stokes G, et al: The reversibility of side effects of guanethidine therapy. Med J Aust 1983;
1:930.
Baumann P, Nil R, Souche A, et al: A double-blind, placebo-controlled study of citalopram with and without lithium
in the treatment of therapy-resistant depressive patients: a clinical, pharmacokinetic, and pharmacogenetic
investigation. J Clin Psychopharmacol 1996; 16:307-314.
Baumann P, Nil R, Souche A, et al: A double-blind, placebo-controlled study of citalopram with and without lithium
in the treatment of therapy-resistant depressive patients: a clinical, pharmacokinetic, and pharmacogenetic
investigation. J Clin Psychopharmacol 1996a; 16:307-314.
Becquemont L, Ragueneau I, Le Bot MA, et al: Influence of the CYP1A2 inhibitor fluvoxamine on tacrine
pharmacokinetics in humans. Clin Pharmacol Ther 1997; 61:619-627.
Becquemont L, Ragueneau I, Le Bot MA, et al: Influence of the CYP1A2 inhibitor fluvoxamine on tacrine
pharmacokinetics in humans. Clin Pharmacol Ther 1997a; 61:619-627.
Beers MH, Ouslander JG, Rollingher I, et al: Explicit criteria for determining inappropriate medication use in
nursing home residents. UCLA Division of Geriatric Medicine. Arch Intern Med 1991; 151(9):1825-1832.
Beers MH: Explicit criteria for determining potentially inappropriate medication use by the elderly. An update. Arch
Intern Med 1997; 157(14):1531-1536.
Benazzi F & Mazzoli M: Polydipsia induced by fluvoxamine. Pharmacopsychiatry 1993; 26:63.
Benazzi F: Nefazodone withdrawal symptoms (letter). Can J Psychiatry 1998; 43(2):194-195.
Benfield P & Ward A: Fluvoxamine: a review of its pharmacodynamic and pharmacokinetic properties, and
therapeutic efficacy in depressive illness. Drugs 1986; 32:313-334.
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 143
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
Filed 03/24/2010
Pageof144
of 160
Page 144
244
Benfield P & Ward A: Fluvoxamine: a review of its pharmacodynamic and pharmacokinetic properties, and
therapeutic efficacy in depressive illness. Drugs 1986a; 32:313-334.
Benfield P & Ward A: Fluvoxamine: a review of its pharmacodynamic and pharmacokinetic properties, and
therapeutic efficacy in depressive illness. Drugs 1986b; 32:313-334.
Berk M & Jacobson BF: Selective serotonin reuptake inhibitor-induced disturbances of haemostasis: mechanisms
and therapeutic implications. CNS Drugs 1998; 10(6):441-446.
Berman JR, Adhikari SP, & Goldstein I: Anatomy and physiology of female sexual function and dysfunction.
Classification, evaluation and treatment options. Eur Urol 2000; 38:20-29.
Berthou F, Flinois JP, Ratanasavanh D, et al: Evidence for the involvement of several cytochromes P-450 in the
first steps of caffeine metabolism by human liver microsomes. Drug Metab Dispos 1991; 19:561-567.
Berthou F, Flinois JP, Ratanasavanh D, et al: Evidence for the involvement of several cytochromes P-450 in the
first steps of caffeine metabolism by human liver microsomes. Drug Metab Dispos 1991a; 19:561-567.
Bertschy G, Vandel S, Vandel G, et al: Fluvoxamine-tricyclic antidepressant interaction: an accidental finding. Eur
J Clin Pharmacol 1991; 40:119-120.
Bertschy G, Vandel S, Vandel G, et al: Fluvoxamine-tricyclic antidepressant interaction: an accidental finding. Eur
J Clin Pharmacol 1991a; 40:119-120.
Bertschy G, Vandel S, Vandel G, et al: Fluvoxamine-tricyclic antidepressant interaction: an accidental finding. Eur
J Clin Pharmacol 1991b; 40:119-120.
Bertschy G, Vandel S, Vandel G, et al: Fluvoxamine-tricyclic antidepressant interaction: an accidental finding. Eur
J Clin Pharmacol 1991c; 40:119-120.
Black DW, Wesner R, & Gabel J: The abrupt discontinuation of fluvoxamine in patients with panic disorder. J Clin
Psychiatry 1993; 54:146-149.
Black DW, Wesner R, Bowers W, et al: A comparison of fluvoxamine, cognitive therapy, and placebo in the
treatment of panic disorder. Arch Gen Psychiatry 1993a; 50:44-50.
Blair JH & Simpson GM: Effects of antipsychotic drugs on the reproductive system. Dis Nerv Syst 1966; 27:645.
Blay SL, Ferraz MPT, & Cacil HM: Lithium-induced male sexual impairment: two case reports. J Clin Psychiatry
1982; 43:497.
Boyden TW, Nugent C, Ogihara T, et al: Reserpine, hydrochlorothiazide and pituitary-gonadal hormones in
hypertensive patients. Eur J Clin Pharmacol 1980; 17:329.
Boyer EW & Shannon M: The serotonin syndrome. N Eng J Med 2005; 352(11):1112-1120.
Bradford LD: Preclinical pharmacology of fluvoxamine (Floxyfrol(R)). Proceedings of the international symposium
on fluvoxamine, Amsterdam, 1984; pp 13-17, September 8-9, 1983.
Brambilla F, Draisci A, & Peirone A: Combined cognitive-behavioral, psychopharmacological and nutritional
therapy in bulimia nervosa. Neuropsychobiology 1995a; 32:68-71.
Brambilla F, Draisci A, Peirone A, et al: Combined cognitive-behavioral, psychopharmacological and nutritional
therapy in bulimia nervosa. Neuropsychobiology 1995; 32:68-71.
Brock GB & Lue TF: Drug-induced male sexual dysfunction. An update. Drug Saf 1993; 8(6):414-426.
Bronner IM & Vanneste JAL: Complex movement disorder associated with fluvoxamine. Mov Disord 1998; 13
(5):848-850.
Bronzo MR & Stahl SM: Galactorrhea induced by sertraline (letter). Am J Psychiatry 1993; 150:1269-1270.
Brown JJ, Davies D, Feriss J, et al: Comparison of surgery and prolonged spironolactone therapy in patients with
hypertension, aldosterone excess, and low plasma renin. Br Med J 1972; 2:729.
Brown WA, Langhren TP, & Williams B: Differential effects of neuroleptic agents on the pituitary-gonadal axis in
men. Arch Gen Psychiatry 1981; 124:420.
Buffum J: Pharmacosexology: the effects of drugs on sexual function, a review. J Psychoactive Drugs 1982; 14:5.
Bulpitt CJ & Dollery CT: Side effects of hypotensive agents evaluated by a self-administered questionnaire. Br
Med J 1973; 3:485.
Bulpitt CJ, Dollery CT, & Carne S: A symptom questionnaire for hypertensive patients. J Chronic Dis 1974; 27:309.
Bulpitt CJ, Dollery CT, & Carne S: Change in symptoms of hypertensive patients after referral to hospital clinic. Br
Heart J 1976; 38:121.
Burnett WC & Chahine RA: Sexual dysfunction as a complication of propranolol therapy in men. Cardiovasc Med
1979; 4:811.
Burrai C, Bocchetta A, & Del Zompo M: Mania and fluvoxamine (letter). Am J Psychiatry 1991; 148:1263.
Burrai C, Bocchetta A, & Del Zompo M: Mania and fluvoxamine (letter). Am J Psychiatry 1991a; 148:1263.
Burrai C, Bocchetta A, & del Zompo M: Mania and fluvoxamine [letter].. Am J Psychiatry 1991b; 148(9):1263-4.
Burrai C, Bochetta A, & Del Zompo M: Mania and fluvoxamine (letter). Am J Psychiat 1991c; 148:1263-1264.
Butler MA, Iwasaki M, Guengerich FP, et al: Human cytochrome P-450PA (P-450IA2), the phenacetin Odemethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic
arylamines. Proc Natl Acad Sci USA 1989; 86(20):7696-7700.
Butler MA, Iwasaki M, Guengerich FP, et al: Human cytochrome P-450PA (P-450IA2), the phenacetin Odemethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic
arylamines. Proc Natl Acad Sci USA 1989a; 86::7696-7700.
Caley CF: Extrapyramidal reactions and the selective serotonin-reuptake inhibitors. Ann Pharmacotherapy 1997;
31:1481-1489.
Canada JR: USP dictionary of USAN and international drug names 1998, The United States Pharmacopeial
Convention, Inc, Rockville, MD, 1997, pp 324.
Carrillo JA, Ramos SI, Herraiz AG, et al: Pharmacokinetic interaction of fluvoxamine and thioridazine in
schizophrenic patients. J Clin Psychopharmacol 1999; 19:494-499.
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 144
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
Filed 03/24/2010
Pageof145
of 160
Page 145
244
Chong SA, Tan CH, & Lee HS: Worsening of psychosis with clozapine and selective serotonin reuptake inhibitor
combination: two case reports. J Clin Psychopharmacol 1997; 17:68-69.
Chong SA, Tan CH, & Lee HS: Worsening of psychosis with clozapine and selective serotonin reuptake inhibitor
combination: two case reports. J Clin Psychopharmacol 1997a; 17:68-69.
Chong SA: Fluvoxamine and mandibular dystonia (letter). Can J Psychiatr 1995; 40:430-431.
Chutka DS , Takahashi PY , & Hoel RW : Inappropriate medications for elderly patients. Mayo Clin Proc 2004; 79
(1):122-139.
Cicero TJ, Bell RD, Wiest WG, et al: Function of the male sex organs in heroin and methadone users. N Engl J
Med 1975; 292:882.
Claassen V, Davies JE, Hertting G, et al: Fluvoxamine, a specific 5-hydroxytryptamine uptake inhibitor. Br J
Pharmacol 1977; 60:505-516.
Claassen V: Review of the animal pharmacology and pharmacokinetics of fluvoxamine. Br J Clin Pharmacol 1983;
15(suppl 3):349S-355S.
Clayton AH, Owens JE, & McGarvey EL: Assessment of paroxetine-induced sexual dysfunction using the changes
in Sexual Functioning Questionnaire. Psychopharmacol Bull 1995; 31(2):397-406.
Clayton DO & Shen WW: Psychotropic drug-induced sexual function disorders. Drug Saf 1998; 19(4):299-312.
Cohen S: Cannabis and sex: multifaceted paradoxes. J Psychoactive Drugs 1982; 14:55.
Cohn JB: Double-blind, multicenter comparison of sertraline and amitriptyline in elderly depressed patients. J Clin
Psychiatry 1990; 51:28-33.
Constantinidis J, Dick P, & Tissot R: Antidepressants and serotonin neurons of the raphe. Neuropsychobiology
1981; 7:113-121.
Cottraux J, Mollard E, Bouvard M, et al: Exposure therapy, fluvoxamine, or combination treatment in obsessivecompulsive disorder: one-year followup. Psychiatr Res 1993; 49:63-75.
Cushman P & Dole V: Detoxification of rehabilitated methadone maintained patients. JAMA 1973; 226:747.
Cushman P: Sexual behavior in heroin addiction and methadone maintenance. New York State J Med 1972;
72:1261.
Dalton S, Johansen C, Mellemkjoer L, et al: Use of selective serotonin reuptake inhibitors and risk of upper
gastrointestinal tract bleeding. Arch Intern Med 2003; 163:59-64.
Dalton S, Johansen C, Mellemkjoer L, et al: Use of selective serotonin reuptake inhibitors and risk of upper
gastrointestinal tract bleeding. Arch Intern Med 2003a; 163:59-64.
Daniel DG, Randolph C, Jaskiw G, et al: Coadministration of fluvoxamine increases serum concentrations of
haloperidol. J Clin Psychopharmacol 1994; 14:340-343.
Daniel DG, Randolph C, Jaskiw G, et al: Coadministration of fluvoxamine increases serum concentrations of
haloperidol. J Clin Psychopharmacol 1994a; 14:340-343.
Davidson JRT, Weisler RH, Malik M, et al: Fluvoxamine in civilians with posttraumatic stress disorder. J Clin
Psychopharmacol 1998; 18:93-95.
De Wilde JE, Mertens C, & Wakelin JS: Clinical trials of fluvoxamine vs chlorimipramine with single and three
times daily dosing. Br J Clin Pharmacol 1983; 15(suppl 3):427S-431S.
De Wilde JE, Mertens C, & Wakelin JS: Clinical trials of fluvoxamine vs chlorimipramine with single and three
times daily dosing. Br J Clin Pharmacol 1983a; 15(Suppl 3):427S-431S.
DeBree H, Van der Schoot JB, & Post LC: Fluvoxamine maleate; disposition in man. Eur J Drug Metab
Pharmacokinet 1983; 8:175-179.
DeBree H, Van der Schoot JB, & Post LC: Fluvoxamine maleate; disposition in man. Eur J Drug Metab
Pharmacokinet 1983a; 8:175-179.
DeVane CL, Ware MR, Emmanuel NP et al: Evaluation of the efficacy, safety and physiological effects of
fluvoxamine in social phobia. Int Clin Psychopharmacol 14:345-351, 1999.
DeWilde JEM & Doogan DP: Fluvoxamine and chlorimipramine in endogenous depression. J Affective Disord
1982; 4:249-259.
Deahl M & Trimble M: Serotonin reuptake inhibitors, epilepsy and myoclonus.. Br J Psychiatry 1991; 159:433-5.
Dean CE: Prasterone (DHEA) and mania. Ann Pharmacother 2000; 34(12):1419-1422.
Dean CE: Prasterone (DHEA) and mania. Ann Pharmacother 2000a; 34(12):1419-1422.
Delgado PL, Goodman WK, Price LH, et al: Fluvoxamine/pimozide treatment of concurrent Tourette's and
obsessive-compulsive disorder. Br J Psychiatry 1990; 157:762-765.
Demers JC & Malone M: Serotonin syndrome induced by fluvoxamine and mirtazapine. Ann Pharmacother 2001;
35:1217-1220.
Diaferia G, Mundo E, Bianchi Y, et al: Behavioral side effects in obsessive-compulsive patients treated with
fluvoxamine: a clinical description. J Clin Psychopharmacol 1994; 14:78-79.
Dick P & Ferrero E: A double-blind comparative study of the clinical efficacy of fluvoxamine and chlorimipramine.
Br J Clin Pharmacol 1983; 15:419S-425S.
Diot P, Jonville AP, Gerard F, et al: Possible interaction between theophylline and fluvoxamine (letter). Therapie
1991; 46:170-171.
Dominguez RA, Goldstein BJ, Jacobson AF, et al: A double-blind placebo-controlled study of fluvoxamine and
imipramine in depression. J Clin Psychiatry 1985; 46:84-87.
Doogan DP: Fluvoxamine as an antidepressant drug. Neuropharmacology 1980; 19:1215-1216.
Doogan DP: Fluvoxamine as an antidepressant drug. Neuropharmacology 1980a; 19:1215-1216.
Dorevitch A, Frankel Y, Bar-Halperin A, et al: Fluvoxamine-associated manic behavior: a case series.. Ann
Pharmacother 1993; 27:1455-7.
Dorman BW & Schmidt JD: Association of priapism in phenothiazine therapy. J Urology 116:51, 1976.
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 145
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
Filed 03/24/2010
Pageof146
of 160
Page 146
244
Dubnov-Raz G, Juurlink DN, Fogelman R, et al: Antenatal use of selective serotonin-reuptake inhibitors and QT
interval prolongation in newborns. Pediatrics 2008; 122(3):e710-e715.
Dudek FA & Turner DJ: Alcoholism and sexual functioning. J Psychoactive Drugs 1982; 14:47.
Duncan L & Bateman DN: Sexual function in women. Do antihypertensive drugs have an impact?. Drug Saf 1993;
8(3):225-234.
Dunn MI & Dunlap JL: Guanadrel. A new antihypertensive drug. JAMA 1981; 245:1639.
Dunner DL, Zisook S, Billow AA, et al: A prospective safety surveillance study for bupropion sustained-release in
the treatment of depression. J Clin Psychiatry 1998; 59:366-373.
Ebringer A, Doyle AE, Dawborn JK, et al: The use of clonidine (Catapres) in the treatment of hypertension. Med J
Aust 1970; 1:524.
Edwards JG & Anderson I: Systematic review and guide to selection of selective serotonin reuptake inhibitors.
Drugs 1999; 57(4):507-533.
Edwards JG, Inman WHW, Wilton L, et al: Prescription#-#event monitoring of 10,401 patients treated with
fluvoxamine. Br J Psychiatry 1994; 164:387-395.
Elwood W: Milnacipran moves in on major depression. Inpharma 1997; 1112:3-4.
Escalona R, Canive JM, Calais LA, et al: Fluvoxamine treatment in veterans with combat-related post- traumatic
stress disorder. Depress Anxiety 2002; 15(1):29-33.
European Porphyria Initiative: Recommendations for the use of drugs in the acute porphyrias (AIP, HCP, VP).
European Porphyria Initiative. Available from URL: www.porphyria-europe.org. As accessed 2/13/06.
Evans M & Marwick P: Fluvoxamine and lithium: an unusual interaction (letter). Br J Psychiatry 1990; 156:286.
FDA Public Health Advisory: Reports of suicidality in pediatric patients being treated with antidepressant
medications for major depressive disorder [MDD] fluvoxamine (October 2003).. Available at:
http://www.fda.gov/cder/drug/advisory/mdd.htm., (October 2003).
FDA Public Health Advisory: Suicidality in Children and Adolescents Being Treated with Antidepressant
Medications.. US Food and Drug Administration. Available at: http://www.fda.gov/cder/drug/antidepressants.htm,
Accessed October 15, 2004.
Fallon BA, Qureshi AI, Schneier FR, et al: An open trial of fluvoxamine for hypochondriasis. Psychosomatics 2003;
44(4):298-303.
Farah A: Relief of SSRI-induced sexual dysfunction with mirtazapine treatment (letter). J Clin Psychiatry 1999; 60
(4):260-261.
Fernando AT III & Schwader P: A case of citalopram withdrawal (letter). J Clin Psychopharmacol 2000; 20(5):581582.
Fick DM, Cooper JW, Wade WE, et al: Updating the Beers criteria for potentially inappropriate medication use in
older adults: results of a US consensus panel of experts. Arch Intern Med 2003; 163(22):2716-2724.
Finger WW & Slagle MA: Changes in sexual function secondary to medication effects. Drugs Today 1998; 34
(4):307-320.
Flament MF & Bisserbe JC: Pharmacologic treatment of obsessive-compulsive disorder: comparative studies. J
Clin Psychiatry 1997; 58(suppl 12):18-22.
Fleeger CA: USP dictionary of USAN and international drug names 1995, The United States Pharmacopeial
Convention, Inc., Rockville, MD, 1994, pp 299.
Fleishaker J, Ryan K, Carel B, et al: Evaluation of the potential pharmacokinetic interaction between almotriptan
and fluoxetine in healthy volunteers. J Clin Pharmacol 2001; 41:217-223.
Forsberg L, Gustavii B, Hojerback T, et al: Impotence, smoking, and beta-blocking drugs. Fertil Steril 1979;
31:589.
Fowler JS, Wang GJ, Volkow ND, et al: Evidence that ginkgo biloba extract does not inhibit MAO A and B in living
human brain. Life Sci 2000; 66(9):141-146.
Franchini L, Gasperini M, & Smeraldi E: A 24-month follow-up study of unipolar subjects: a comparison between
lithium and fluvoxamine. Journal of Affective Disorders 1994; 32:226-231.
Franchini L, Gasperini M, Perez J, et al: A double-blind study of long-term treatment with sertraline or fluvoxamine
for prevention of highly recurrent unipolar depression. J Clin Psychiatry 1997; 58:104-107.
Franchini L, Zanardi R, Gasperini M, et al: Fluvoxamine and lithium in long-term treatment of unipolar subjects whit
high recurrence rate. J Affect Disord 1996; 38:67-69.
Franks S, Jacobs HS, Martin N, et al: Hyperprolactinaemia and impotence. Clin Endocrinol 1978; 8:277.
Freeman CP, Trimble MR, Deakin JF, et al: Fluvoxamine versus clomipramine in the treatment of obsessive
compulsive disorder: a multicenter, randomized, double-blind, parallel group comparison. J Clin Psychiatry 1994;
55:301-305.
Freeman EW, Rickels K, & Sondheimer SJ: Fluvoxamine for premenstrual dysphoric disorder: a pilot study. J Clin
Psychiatry 1996; 57(Suppl 8):56-59.
Fritze J, Unsorg B, & Lanczik M: Interaction between carbamazepine and fluvoxamine. Acta Psychiatr Scand
1991; 84:583-584.
Fritze J, Unsorg B, & Lanczik M: Interaction between carbamazepine and fluvoxamine. Acta Psychiatr Scand
1991a; 84:583-584.
Frost L & Lal S: Shock-like sensations after discontinuation of selective serotonin reuptake inhibitors (letter). Am J
Psychiatry 1995; 152:810.
Fukuchi T & Kanemoto K: Differential effects of milnacipran and fluvoxamine, especially in patients with severe
depression and agitated depression: a case-control study. Int Clin Psychopharmacol 2002; 17(2):53-58.
Fuller RW & Wong DT: Serotonin reuptake blockers in vitro and in vivo. J Clin Psychopharmacol 1987; 7:36S-43S.
Furusho J, Matsuzaki K, Ichihashi I, et al: Alleviation of sleep disturbance and repetitive behavior by a selective
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 146
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
152.
153.
154.
155.
156.
157.
158.
159.
160.
161.
162.
163.
164.
165.
166.
167.
168.
169.
170.
171.
172.
173.
174.
175.
176.
177.
178.
179.
180.
181.
182.
183.
184.
185.
186.
Filed 03/24/2010
Pageof147
of 160
Page 147
244
serotonin re-uptake inhibitor in a boy with Asperger's syndrome. Brain Dev 2001; 23:135-137.
Garbutt G & Goldstein A: "Blind comparison of three methadone maintenance dosages in 180 patients" In:
Proceedings of the Fourth National Conference on Methadone Treatment. New York: National Association for
Prevention of addiction to Narcotics. ; 411, 1972.
Gasperini M, Gatti F, Bellini L, et al: Perspectives in clinical psychopharmacology of amitriptyline and fluvoxamine:
a double-blind study in depressed inpatients. Pharmacopsychiatry 1992; 26:186-192.
Gatti F, Bellini L, Gasperini M, et al: Fluvoxamine alone in the treatment of delusional depression. Am J Psychiatry
1996; 153:414-416.
Gentile S: Quetiapine-fluvoxamine combination during pregnancy and while breastfeeding. Arch Womens Ment
Health 2006; 9(3):158-159.
George MS & Trimble MR: A fluvoxamine-induced frontal lobe syndrome in a patient with comorbid gilles de la
tourette's syndrome and obsessive compulsive disorder (letter). J Clin Psychiatry 1992; 53:379.
George MS & Trimble MR: Dystonic reaction associated with fluvoxamine. J Clin Psychopharm 1993; 13:220-221.
Gill HS, DeVane CL, & Risch SC: Extrapyramidal symptoms associated with cyclic antidepressant treatment: a
review of the literature and consolidating hypotheses. J Clin Psychopharmacol 1997; 17:377-389.
Gill M, LoVecchio F, & Selden B: Serotonin syndrome in a child after a single dose of fluvoxamine. Ann Emerg
Med 1999; 33:457-459.
Gonella G, Gaignoli G, & Ecari U: Fluvoxamine and imipramine in the treatment of depressive patients: a doubleblind controlled study. Curr Med Res Opin 1990; 12:177-184.
Goodman WK, Price LH, Delgado PL, et al: Specificity of serotonin reuptake inhibitors in the treatment of
obsessive-compulsive disorder.. Arch Gen Psychiatry 1990; 47:577-85.
Gordon GG, Altman K, Southren L, et al: The effect of alcohol (ethanol) administration on sex-hormone
metabolism in normal men. N Engl J Med 1976; 295:793.
Gordon JB: SSRIs and St. John's Wort: possible toxicity (letter)?. Am Fam Physician 1998a; 57:950-951.
Gordon JB: SSRIs and St. John's wort: possible toxicity?. Am Fam Physician 1998; 57:950-951.
Graber MA, Hoehns TB, & Perry PJ: Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann
Pharmacother 1994; 28:732-735.
Graber MA, Hoehns TB, & Perry PJ: Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann
Pharmacother 1994a; 28:732-735.
Graber MA, Hoehns TB, & Perry PJ: Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann
Pharmacother 1994b; 28:732-735.
Graber MA, Hoehns TB, & Perry PJ: Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann
Pharmacother 1994c; 28:732-735.
Graber MA, Hoehns TB, & Perry PJ: Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann
Pharmacother 1994d; 28:732-735.
Graber MA, Hoehns TB, & Perry PJ: Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann
Pharmacother 1994e; 28:732-735.
Graber MA, Hoehns TB, & Perry PJ: Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann
Pharmacother 1994f; 28:732-735.
Graber MA, Hoehns TB, & Perry PJ: Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann
Pharmacother 1994g; 28:732-735.
Graber MA, Hoehns TB, & Perry PJ: Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann
Pharmacother 1994h; 28:732-735.
Graber MA, Hoehns TB, & Perry PJ: Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann
Pharmacother 1994i; 28:732-735.
Graber MA, Hoehns TB, & Perry PJ: Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann
Pharmacother 1994j; 28:732-735.
Graber MA, Hoehns TB, & Perry PJ: Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann
Pharmacother 1994k; 28:732-735.
Graber MA, Hoehns TB, & Perry PJ: Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann
Pharmacother 1994l; 28:732-735.
Graber MA, Hoehns TB, & Perry PJ: Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann
Pharmacother 1994m; 28:732-735.
Graber MA, Hoehns TB, & Perry PJ: Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann
Pharmacother 1994n; 28:732-735.
Graber MA, Hoehns TB, & Perry PJ: Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann
Pharmacother 1994o; 28:732-735.
Graber MA, Hoehns TB, & Perry PJ: Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann
Pharmacother 1994p; 28:732-735.
Graber MA, Hoehns TB, & Perry PJ: Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann
Pharmacother 1994q; 28:732-735.
Graber MA, Hoehns TB, & Perry PJ: Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann
Pharmacother 1994r; 28:732-735.
Graber MA, Hoehns TB, & Perry PJ: Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann
Pharmacother 1994s; 28:732-735.
Gram LF, Hansen MGJ, Sindrup SH, et al: Citalopram: interaction studies with levomepromazine, imipramine, and
lithium. Ther Drug Monit 1993; 15:18-24.
Gram LF, Hansen MGJ, Sindrup SH, et al: Citalopram: interaction studies with levomepromazine, imipramine, and
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 147
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
187.
188.
189.
190.
191.
192.
193.
194.
195.
196.
197.
198.
199.
200.
201.
202.
203.
204.
205.
206.
207.
208.
209.
210.
211.
212.
213.
214.
215.
216.
217.
218.
219.
220.
221.
222.
Filed 03/24/2010
Pageof148
of 160
Page 148
244
lithium. Ther Drug Monit 1993a; 15:18-24.
Granfors MT, Backman JT, Neuvonen M, et al: Fluvoxamine drastically increases concentrations and effects of
tizanidine: a potentially hazardous interaction.. Clin Pharmacol Ther 2004; 75:331-341.
Grant DM, Campbell ME, Tang BK, et al: Biotransformation of caffeine by microsomes from human liver. Kinetics
and inhibition studies. Biochem Pharmacol 1987; 36:1251-1260.
Grant DM, Campbell ME, Tang BK, et al: Biotransformation of caffeine by microsomes from human liver. Kinetics
and inhibition studies. Biochem Pharmacol 1987a; 36:1251-1260.
Grassi B, Gambini O, & Scarone S: Notes on the of fluvoxamine as treatment of depression in HIV-1-infected
subjects. Pharmacopsychiatry 1995; 28:93-94.
Green BH: Fluvoxamine and hepatic function (letter). Br J Psychiatr 1988; 153:130-131.
Grimsley SR & Jann MW: Paroxetine, sertraline, and fluvoxamine: new selective serotonin reuptake inhibitors. Clin
Pharm 1992; 11:930-957.
Grimsley SR & Jann MW: Paroxetine, sertraline, and fluvoxamine: new selective serotonin reuptake inhibitors. Clin
Pharm 1992a; 11:930-957.
Gross MD: Reversal by bethanechol of sexual dysfunction caused by anticholinergic antidepressants. Am J
Psychiatry 1982; 139:1193.
Gu L, Gonzalez FJ, Kalow W, et al: Biotransformation of caffeine, paraxanthine, theobromine and theophylline by
cDNA-expressed human CYP1A2 and CYP 2E1. Pharmacogenetics 1992; 2:73-77.
Gu L, Gonzalez FJ, Kalow W, et al: Biotransformation of caffeine, paraxanthine, theobromine and theophylline by
cDNA-expressed human CYP1A2 and CYP 2E1. Pharmacogenetics 1992a; 2:73-77.
Guelfi JD, Ansseau M, Corruble E, et al: A double-blind comparison of the efficacy and safety of milnacipran and
fluoxetine in depressed inpatients. Intern Clin Psychopharmacol 1998; 13:121-128.
Guelfi JD, Dreyfus JF, Pichot P, et al: A double-blind controlled clinical trial comparing fluvoxamine with
imipramine. Br J Clin Pharmacol 1983; 15:411S-417S.
Guelfi JD, Dreyfus JF, Pichot P, et al: A double-blind controlled clinical trial comparing fluvoxamine with
imipramine. Br J Clin Pharmacol 1983a; 15:411S-417S.
Guy W, Wilson WH, Ban TA, et al: A double-blind clinical trial of fluvoxamine and imipramine in patients with
primary depression. Psychopharmacol Bull 1984; 20:73-78.
Haddad PM: Antidepressant discontinuation syndromes. Drug Saf 2001; 24(3):183-197.
Halikas J, Weller R, & Morse C: Effects of regular marijuana use on sexual performance. J Psychoactive Drugs
1982; 14:59.
Hamilton BA, Jones PG, Hoda AN, et al: Flupenthixol and fluvoxamine in mild to moderate depression: a
comparison in general practice. Pharmatherapeutica 1989; 5:292-297.
Handson L, Paschal A, & Julius S: Comparison of guanadrel and guanethidine. Clin Pharmacol Ther 1973;
14:204.
Harmon J & Aliapoulious MA: Gynecomastia in marihuana users. N Engl J Med 1972; 287:936.
Harten J: Overview of the pharmacokinetics of fluvoxamine.. Clin Pharmacokinet 1995; 29 Suppl 1:1-9.
Hartter S, Grozinger M, Weigmann H, et al: Increased bioavailability of oral melatonin after fluvoxamine
coadministration. Clin Pharmacol Ther 2000; 67:1-6.
Hartter S, Grozinger M, Weigmann H, et al: Increased bioavailability of oral melatonin after fluvoxamine
coadministration. Clin Pharmacol Ther 2000a; 67(1):1-6.
Hartter S, Wetzel H, Hammes E, et al: Inhibition of antidepressant demethylation and hydroxylation by fluvoxamine
in depressed patients. Psychopharmacology 1993; 110:302-308.
Hartter S, Wetzel H, Hammes E, et al: Inhibition of antidepressant demethylation and hydroxylation by fluvoxamine
in depressed patients. Psychopharmacology 1993a; 110:302-308.
Hartter S, Wetzel H, Hammes E, et al: Inhibition of antidepressant demethylation and hydroxylation by fluvoxamine
in depressed patients. Psychopharmacology 1993b; 110:302-308.
Hartter S, Wetzel H, Hammes E, et al: Inhibition of antidepressant demethylation and hydroxylation by fluvoxamine
in depressed patients. Psychopharmacology 1993c; 110:302-308.
Hartter S, Wetzel H, Hammes E, et al: Inhibition of antidepressant demethylation and hydroxylation by fluvoxamine
in depressed patients. Psychopharmacology 1993d; 110:302-308.
Hartter S, Wetzel H, Hammes E, et al: Inhibition of antidepressant demethylation and hydroxylation by fluvoxamine
in depressed patients. Psychopharmacology 1993e; 110:302-308.
Hartter S, Wetzel H, Hammes E, et al: Inhibition of antidepressant demethylation and hydroxylation by fluvoxamine
in depressed patients. Psychopharmacology 1993f; 110:302-308.
Hartter S, Wetzel H, Hammes E, et al: Inhibition of antidepressant demethylation and hydroxylation by fluvoxamine
in depressed patients. Psychopharmacology 1993g; 110:302-308.
Heel R, Brogden R, Speight T, et al: Atenolol: a review of its pharmacological and therapeutic efficacy in angina
pectoris and hypertension. Drugs 1979; 17:425.
Hembree WC: Marijuana effects upon the human testes. Clin Res 1976; 24:272A.
Hiemke C, Peled A, Jabarin M, et al: Fluvoxamine augmentation of olanzapine in chronic schizophrenia:
pharmacokinetic interactions and clinical effects. J Clin Psychopharmacol 2002; 22(5):502-506.
Hirschfeld RMA: Management of sexual side effects of antidepressant therapy. J Clin Psychiatry 1999; 60(suppl
14):27-30.
Hoehn-Saric R, Lipsey JR, & McLeod DR: Apathy and indifference in patients on fluvoxamine and fluoxetine. J
Clin Psychopharmacol 1990; 10:343-345.
Hogan MJ, Wallin JK, & Baer RM: Antihypertensive therapy and male sexual dysfunction. Psychosomatics 1980;
21:234.
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 148
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
223.
224.
225.
226.
227.
228.
229.
230.
231.
232.
233.
234.
235.
236.
237.
238.
239.
240.
241.
242.
243.
244.
245.
246.
247.
248.
249.
250.
251.
252.
253.
254.
255.
256.
257.
Filed 03/24/2010
Pageof149
of 160
Page 149
244
Hohagen F, Winkelmann G, Rasche-Rauchle H, et al: Combination of behaviour therapy with fluvoxamine in
comparison with behaviour therapy and placebo: results of a multicentre study. Br J Psychiatr 1998; 173(suppl
35):71-78.
Holland OB, Fairchild C, & Gomez-Sanchez GE: Effect of guanabenz and hydrochlorothiazide on blood pressure
and plasma renin activity. J Clin Pharmacol 1981; 21:133.
Hollander E, DeCaria C, Mari E, et al: Short-term single-blind fluvoxaine treatment of pathological gambling. Am J
Psychiatry 1998; 155:1781-1783.
Hollander E, Koran LM, Goodman WK, et al: A double-blind, placebo-controlled study of the efficacy and safety of
controlled-release fluvoxamine in patients with obsessive-compulsive disorder. J Clin Psychiatry 2003; 64(6):640647.
Hollifield JW, Sherman K, Vander Zwagg R, et al: Proposed mechanisms of propranolol's antihypertensive effect
in essential hypertension. N Engl J Med 1976; 295:68.
Hori H, Yoshimura R, Ueda N, et al: Grapefruit juice-fluvoxamine interaction. Is it risky or not?. J Clin
Psychopharmacol 2003; 23(3):422-424.
Hori H, Yoshimura R, Ueda N, et al: Grapefruit juice-fluvoxamine interaction. Is it risky or not?. J Clin
Psychopharmacol 2003a; 23(3):422-424.
Horowitz JD & Goble AJ: Drugs and impaired male sexual function. Drugs 1979; 18:206.
Howard JS: Severe psychosis and the adrenal androgens. Integr Physiol Behav Sci 1992; 27(3):209-215.
Huang HFS, Nahas GG, & Hembree WC: Morphological changes of spermatozoa during marihuana induced
depression of human spermatogenesis (abstract). Fed Proc 1978; 37:739.
Hudson JI, Carter WP, & Pope HC Jr: Antidepressant treatment of binge-eating disorder: research findings and
clinical guidelines. J Clin Psychiatry 1996; 57(suppl 8):73-79.
Hudson JI, McElroy SL, Raymond NC, et al: Fluvoxamine in the treatment of binge-eating disorder: a multicenter
placebo-controlled, double-blind trial. Am J Psychiatry 1998; 155:1756-1762.
Isbister GK, Dawson AH, & Whyte IM: Comment: serotonin syndrome induced by fluvoxamine and mirtazapine.
Ann Pharmacother 2001; 35(12):1674-1675.
Itil TM, Shrivastava RK, Mukherjee S, et al: A double-blind placebo-controlled study of fluvoxamine and
imipramine in out-patients with primary depression. Br J Clin Pharmacol 1983; 15:433S-438S.
Jabbari B: Incidence of seizures with tricylcic and tetracyclic antidepressants. Arch Neurol 1985; 42:480-481.
Jackson BA: Nadolol, a once daily treatment for hypertension multi-centre clinical evaluation. Br J Clin Pract 1980;
34:211.
Janahyala BS, Clarke DE, & Buckley JP: The effects of prolonged administration of certain antihypertensive
agents. J Pharm Sci 1974; 63:1497.
Jano E & Aparasu RR : Healthcare outcomes associated with beers' criteria: a systematic review. Ann
Pharmacother 2007; 41(3):438-447.
Jefferson JW, Griest JH, Perse TL, et al: Fluvoxamine-associated mania/hypomania in patients with obsessivecompulsive disorder (letter). J Clin Psychopharmacol 1991; 11:391-392.
Jeffries J, Bezchilbnyk-Butler K, & Remington G: Amenorrhea and galactorrhea associated with fluvoxamine in a
loxapine-treated patient (letter). J Clin Psychopharmacol 1992; 12:296-297.
Jenike MA, Hyman S, Baer L, et al: A controlled trial of fluvoxamine in obsessive-compulsive disorder: implications
for a serotonergic theory.. Am J Psychiatry 1990; 147(9):1209-15.
Jensen J, Lendorf A, Stimpel H, et al: The prevalence and etiology of impotence in 101 male hypertensive
outpatients. Am J Hypertens 1999; 12:271-275.
Jeppesen U, Loft S, Poulsen HE, et al: Fluvoxamine-caffeine interaction study. Pharmacogenetics 1996; 6:213222.
Jeppesen U, Loft S, Poulsen HE, et al: Fluvoxamine-caffeine interaction study. Pharmacogenetics 1996a; 6:213222.
Jeppesen U, Loft S, Poulsen HE, et al: Fluvoxamine-caffeine interaction study. Pharmacogenetics 1996b; 6:213222.
Jeppesen U, Loft S, Poulsen HE, et al: Fluvoxamine-caffeine interaction study. Pharmacogenetics 1996c; 6:213222.
Jerling M, Lindstrom L, Bondesson U, et al: Fluvoxamine inhibition and carbamazepine induction of the
metabolism of clozapine: evidence from a therapeutic drug monitoring service. Ther Drug Monit 1994; 16:368-374.
Jerling M, Lindstrom L, Bondesson U, et al: Fluvoxamine inhibition and carbamazepine induction of the
metabolism of clozapine: evidence from a therapeutic drug monitoring service. Ther Drug Monit 1994a; 16:368374.
Jick H: Tricyclic antidepressants and convulsions. J Clin Psychopharmacol 1983; 3:182-185.
Jimenez-Jimenez FJ, Orti-Pareja M, & Zurdo JM: Aggravation of glaucoma with fluvoxamine. Ann Pharmacother
2001; 35:1565-1566.
Joffe RT, Levitt AJ, Sokolov STH, et al: Response to an open trial of a second SSRI in major depression. J Clin
Psychiatry 1996; 57:114-115.
Johnson CD, Reeves KO, & Jackson D: Alcohol and sex. Heart Lung 1983; 12:93.
Johnson MR, Lydiard RB, Morton WA, et al: Effect of fluvoxamine, imipramine and placebo on catecholamine
function in depressed outpatients. J Psychiat Res 1993; 27:161-172.
Jokinen M, Ahonen J, Neuvonen P, et al: The effect of erythromycin, fluvoxamine, and their combination on the
pharmacokinetics of ropivacaine. Anesth Analg 2000; 91:1207-1212.
Jokinen M, Ahonen J, Neuvonen P, et al: The effect of erythromycin, fluvoxamine, and their combination on the
pharmacokinetics of ropivacaine. Anesth Analg 2000a; 91:1207-1212.
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 149
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
258.
259.
260.
261.
262.
263.
264.
265.
266.
267.
268.
269.
270.
271.
272.
273.
274.
275.
276.
277.
278.
279.
280.
281.
282.
283.
284.
285.
286.
287.
288.
289.
290.
291.
292.
293.
294.
Filed 03/24/2010
Pageof150
of 160
Page 150
244
Karunatilake H & Buckley NA: Serotonin syndrome induced by fluvoxamine and oxycodone. Ann Pharmacother
2006; 40(1):155-157.
Keidan H: Impotence during antihypertensive treatment. Can Med Assoc J 1976; 114:874.
Kennedy SH, Eisfeld BS, Dickens SE, et al: Antidepressant-induced sexual dysfunction during treatment with
moclobemide, paroxetine, sertraline, and venlafaxine. J Clin Psychiatry 2000; 61:276-281.
Khan A, Camel G, & Perry HMJ: Clonidine (Catapres): a new antihypertensive agent. Curr Ther Res 1970; 12:10.
Kiev A & Feiger A: A double-blind comparison of fluvoxamine and paroxetine in the treatment of depressed
outpatients. J Clin Psychiatry 1997; 58:146-152.
Kim KY, Craig JM, & Hawley JM: Seizure possibly associated with fluvoxamine. Ann Pharmacother 2000;
34:1276-1278.
Kinsey AC, Pomeroy WB, & Martin CE: Sexual behavior in the human male, Saunders, Philadelphia, 1948.
Klok CJ, Brouwer GJ, van Praag HM, et al: Fluvoxamine and clomipramine in depressed patients: a double-blind
clinical study. Acta Psychiatr Scand 1981; 64:1-11.
Knarr JW: Impotence from propranolol?. Ann Intern Med 1976; 85:259.
Kolodny RC, Masters WH, Hendryx J, et al: Plasma testosterone and semen analysis in male homosexuals. N
Engl J Med 1971; 285:1170.
Kolodny RC, Masters WH, Kolodner RM, et al: Depression of plasma testosterone levels after chronic intensive
marihuana use. N Engl J Med 1974; 290:872.
Kotin J, Wilbert DE, Verburg D, et al: Thioridazine and sexual dysfunction. Am J Psychiatry 1976; 133:82.
Kranzler HR, Del Boca F, Korner P, et al: Adverse effects limit the usefulness of fluvoxamine for the treatment of
alcoholism. J Subst Abuse Treat 1993; 10:283-287.
Kristensen JH, Hackett LP, Kohan R, et al: The amount of fluvoxamine in milk is unlikely to be a cause of adverse
effects in breastfed infants. J Hum Lact 2002; 18(2):139-143.
Kulin NA, Pastuszak A, Sage SR, et al: Pregnancy outcome following maternal use of the new selective serotonin
reuptake inhibitors: a prospective controlled multicenter study. JAMA 1998; 279:609-610.
Kuo FJ, Lane HY, & Chang WH: Extrapyramidal symptoms after addition of fluvoxamine to clozapine (letter). J
Clin Psychopharmacol 1998; 18:483-484.
Kuo FJ, Lane HY, & Chang WH: Extrapyramidal symptoms after addition of fluvoxamine to clozapine (letter). J
Clin Psychopharmacol 1998a; 18:483-484.
Kusumoto M, Kazuyuki U, Oda A, et al: Effect of fluvoxamine on the pharmacokinetics of mexiletine in healthy
Japanese men. Clin Pharmacol Ther 2001; 69:104-107.
Kusumoto M, Kazuyuki U, Oda A, et al: Effect of fluvoxamine on the pharmacokinetics of mexiletine in healthy
Japanese men. Clin Pharmacol Ther 2001a; 69:104-107.
Laird LK, Lydiard RB, Morton WA, et al: Cardiovasculareffects of imipramine, fluvoxamine, and placebo in
depressed outpatients. J Clin Psychiatry 1993; 54:224-228.
Lang AB, Goeckner DJ, Adesso VJ, et al: Effects of alcohol on aggression in male social drinkers. J Abnorm
Psychol 1975; 84:508.
Lantz MS, Buchalter E, & Giambanco V: St. John's Wort and antidepressant drug interactions in the elderly. J
Geriatr Psychiatry Neurol 1999; 12:7-10.
Lantz MS, Buchalter E, & Giambanco V: St. John's Wort and antidepressant drug interactions in the elderly. J
Geriatr Psychiatry Neurol 1999a; 12:7-10.
Lapierre YD, Browne M, Horn E, et al: Treatment of major affective disorder with fluvoxamine. J Clin Psychiatry
1987; 48:65-68.
Lapierre YD, Rastogi RB, & Singhal RL: Fluvoxamine influences serotonergic system in the brain: neurochemical
evidence. Neuropsychobiology 1983; 10:213-216.
Lappin RI & Auchincloss EL: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 1994;
331:1021-1022.
Lappin RI & Auchincloss EL: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 1994a;
331:1021-1022.
Lappin RI & Auchincloss EL: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 1994b;
331:1021-1022.
Lappin RI & Auchincloss EL: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 1994c;
331:1021-1022.
Lappin RI & Auchincloss EL: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 1994d;
331:1021-1022.
Lappin RI & Auchincloss EL: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 1994e;
331:1021-1022.
Lappin RI & Auchincloss EL: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 1994f;
331:1021-1022.
Lappin RI & Auchincloss EL: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 1994g;
331:1021-1022.
Lappin RI & Auchincloss EL: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 1994h;
331:1021-1022.
Lappin RI & Auchincloss EL: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 1994i;
331:1021-1022.
Lappin RI & Auchincloss EL: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 1994j;
331:1021-1022.
Lappin RI & Auchincloss EL: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 1994k;
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 150
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
295.
296.
297.
298.
299.
300.
301.
302.
303.
304.
305.
306.
307.
308.
309.
310.
311.
312.
313.
314.
315.
316.
317.
318.
319.
320.
321.
322.
323.
324.
325.
326.
327.
328.
329.
330.
331.
Filed 03/24/2010
Pageof151
of 160
Page 151
244
331:1021-1022.
Lappin RI & Auchincloss EL: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 1994l;
331:1021-1022.
Lappin RI & Auchincloss EL: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 1994m;
331:1021-1022.
Lappin RI & Auchincloss EL: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 1994n;
331:1021-1022.
Lappin RI & Auchincloss EL: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 1994o;
331:1021-1022.
Lappin RI & Auchincloss EL: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 1994p;
331:1021-1022.
Lappin RI & Auchincloss EL: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 1994q;
331:1021-1022.
Lappin RI & Auchincloss EL: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 1994r;
331:1021-1022.
Lappin RI & Auchincloss EL: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 1994s;
331:1021-1022.
Laws D, Ashford JJ, & Anstee JA: A multicentre double-blind comparative trial fluvoxamine versus lorazepam in
mixed anxiety and depression treated in general practice. Acta Psychiatr Scand 1990; 81:185-189.
Lazowick AL & Levin GM: Potential withdrawal syndrome associated with SSRI discontinuation. Ann
Pharmacother 1995; 29:1284-1285.
Lee M & Sharifi R: More on drug-induced sexual dysfunction. Clin Pharm 1982; 1:397.
Leiter FL, Nierenberg AA, Sanders KM, et al: Discontinuation reactions following sertraline. Biol Psychiatry 1995;
38:694-695.
Lelo A, Miners JO, Robson RA, et al: Quantitative assessment of caffeine partial clearances in man. Br J Clin
Pharmacol 1986; 22:183-186.
Lelo A, Miners JO, Robson RA, et al: Quantitative assessment of caffeine partial clearances in man. Br J Clin
Pharmacol 1986a; 22:183-186.
Lemere F & Smith JW: Alcohol induced sexual impotence. Am J Psychiatry 1973; 130:212.
Leonard HL: New developments in the treatment of obsessive-compulsive disorder. J Clin Psychiatry 1997; 58
(suppl 14):39-45.
Lesch KP, Wolozin BL, Murphy DL, et al: Primary structure of the human platelet serotonin uptake site: identity
with the brain serotonin transporter. J Neurochem 1993; 60(6):2319-2322.
Levine SB: Marital sexual dysfunction: introductory concepts. Ann Intern Med 1976; 84:448.
Lopez-Ibor J, Guelfi JD, Pletan Y, et al: Milnacipran and selective serotonin reuptake inhibitors in major
depression. Intern Clin Psychopharmacol 1996; 11(suppl 4):41-46.
Lorenz C, Brueggmann J, Eberhardt C, et al: Der klinisch-pharmazeutische Fall. Arzneimittelinteraktion von
Fluvoxamin mit Theophyllin. Krankenhauspharmazie 1996; 9:448-451.
Lorenz C, Brueggmann J, Eberhardt C, et al: Der klinisch-pharmazeutische Fall. Arzneimittelinteraktion von
Fluvoxamin mit Theophyllin. Krankenhauspharmazie 1996a; 9:448-451.
Loriaux DL, Menard R, Taylor A, et al: Spironolactone and endocrine dysfunction. Ann Intern Med 1976; 85:630.
Louie AK, Lannon RA, & Ajari LJ: Withdrawal reaction after sertraline discontinuation (letter). Am J Psychiatry
1994; 151:450-451.
Lucca A, Lucini V, Catalano M, et al: Plasma tryptophan to large neutral amino acids ratio and therapeutics
response to selective serotonin uptake inhibitors. Neuropsychobiology 1994; 29:108-111.
Luvox package insert (Solvay—US). Rev Rec 5/97., 3/97.
Luvox product monograph.. Solvay Kingswood—Canada., Rev 10/19/93, Rec 11/20/95.
Lydiard RB, Laird LK, Morton WA, et al: Fluvoxamine, imipramine and placebo in the treatment of depressed
outpatients: effects on depression. Psychopharmacol Bull 1989; 25:68-70.
Majewska MD: Neuronal actions of dehydroepiandrosterone: possible roles in brain development, aging, memory
and affect. Ann NY Acad Sci 1995; 774:111-120.
Malatynska E: Antidepressants and seizure-interactions at the GABA receptor chloride-ionophore complex. Life
Sci 1988; 43:303-307.
Mallya G, White K, & Gunderson C: Is there a serotonergic withdrawal syndrome? (letter). Biol Psychiatry 1993;
33:851-852.
Malm H, Klaukka T, & Neuvonen PJ: Risks Associated With Selective Serotonin Reuptake Inhibitors in Pregnancy.
Obstet Gynecol 2005; 106(6):1289-1296.
Mamiya K, Kojima K, Yukawa E, et al: Phenytoin intoxication induced by fluvoxamine. Ther Drug Monit 2000;
23:75-77.
Markowitz JS, Carson WH, & Jackson CW: Possible dehydroepiandrosterone-induced mania. Biol Psychiatry
1999; 45:241-242.
Marlatt GA, Demming B, & Reid JB: Loss of control drinking in alcoholics: an experimental analogue. J Abnorm
Psychol 1973; 81:233.
Marmar CR, Schoenfeld F, Weiss DS, et al: Open trial of fluvoxamine treatment for combat-related posttraumatic
stress disorder. J Clin Psychiatry 1996; 57(suppl 8):66-72.
Marshall EJ: Why patients do not take their medication. Am J Psychiatry 1971; 128:656.
Martin AJ, Tebbs VM, & Ashford JJ: Affective disorders in general practice. Treatment of 6000 patients with
fluvoxamine. Pharmatherapeutica 1987; 5:40-49.
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 151
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
332.
333.
334.
335.
336.
337.
338.
339.
340.
341.
342.
343.
344.
345.
346.
347.
348.
349.
350.
351.
352.
353.
354.
355.
356.
357.
358.
359.
360.
361.
362.
363.
364.
365.
366.
367.
368.
Filed 03/24/2010
Pageof152
of 160
Page 152
244
Martin AJ, Tebbs VM, & Ashford JJ: Affective disorders in general practice. Treatment of 6000 patients with
fluvoxamine. Pharmatherapeutica 1987a; 5:40-49.
Martinelli V, Bocchetta A, Palmas AM, et al: An interaction between carbamazepine and fluvoxamine (letter). Br J
Clin Pharmacol 1993; 36:615-616.
Masters WH & Johnson VE: Human sexual inadequacies, Little & Brown, Boston, 1979.
McDougle CJ, Goodman WK, Leckman JF, et al: Haloperidol addition in fluvoxamine-refractory obsessivecompulsive disorder. Arch Gen Psychiatry 1994; 51:302-308.
McDougle CJ, Naylor ST, Cohen DJ, et al: A double-blind, placebo-controlled study of fluvoxamine in adults with
autisitc disorder. Arch Gen Psychiatry 1996; 53:1001-1008.
McHardy KC: Syndrome of inappropriate antidiuretic hormone secretion due to fluvoxamine therapy. Br J Clin
Pract 1993; 47:62-63.
McMahon CD, Shaffer RN, Hoskins HD, et al: Adverse effects experienced by patient taking timolol. Am J
Opthalmol 1979; 88:736.
McMahon FG: Management of essential hypertension, Furtura Publishing, New York, 1978, pp 194.
McManis PG & Talley NJ: Nausea and vomiting associated with selective serotonin reuptake inhibitors - incidence,
mechanism and management. CNS Drugs 1997; 8:394-401.
Meinhardt W, Kropman RF, Vermeij P, et al: The influence of medication on erectile function. Int J Impot Res
1997; 9:17-26.
Melman A & Gingell JC: The epidemiology and pathophysiology of erectile dysfunction. J Urol 1999; 161:5-11.
Meltzer H, Bastani B, Jayathilake K, et al: Fluoxetine, but not tricyclic antidepressants, potentiates the 5hydroxytryptophan-mediated increase in plasma cortisol and prolactin secretion in subjects with major depression
or with obsessive compulsive disorder. Neuropsychopharmacology 1997; 17(1):1-11.
Meltzer H, Bastani B, Jayathilake K, et al: Fluoxetine, but not tricyclic antidepressants, potentiates the 5hydroxytryptophan-mediated increase in plasma cortisol and prolactin secretion in subjects with major depression
or with obsessive compulsive disorder. Neuropsychopharmacology 1997a; 17(1):1-11.
Mendelson JH, Ellingboe J, Keuhnle JC, et al: Effect of naltrexone on mood and neuroendocrine function in
normal adult males. Psychoneuroendocrinology 1978; 3:231.
Mendelson JH, Kuehnle J, Ellingboe J, et al: Plasma testosterone levels before, during and after chronic
marihuana smoking. N Engl J Med 1974; 291:1051.
Mendelson JH, Mello NK, & Ellingboe J: Effects of acute alcohol intake on pituitary-gonadal hormones in normal
human males. J Pharmacol Exp Ther 1977; 202:676.
Michael A, Tubbe PA, & Praseedom A: Sertraline-induced anorgasmia reversed by nefazodone. Br J Psychiatry
1999; 175(Nov):491.
Milanfranchi A, Ravagli S, Lensi P, et al: A double-blind study of fluvoxamine and clomipramine in the treatment of
obsessive-compulsive disorder. Int Clin Psychopharmacol 1997; 12:131-136.
Mills LC: Drug-induced impotence. Am Fam Physician 1975; 12:104.
Mintz J, O'Hare K, & O'Brien CP: Sexual problems of heroin addicts. Arch Gen Psychiatry 1974; 31:700.
Mirin SM, Meyer RE, Mendelson JH, et al: Opiate use and sexual function. Am J Psychiatry 1980; 137:909.
Mitchell JE & Popkin MK: Antidepressant drug therapy and sexual dysfunction in men: a review. J Clin
Psychopharmacol 1983; 3:76.
Mitchell JE & Popkin MK: Antipsychotic drug therapy and sexual dysfunction in men. Am J Psychiatry 1982;
139:633.
Momo K, Doki K, Hosono H, et al: Drug Interaction of tizanidine and fluvoxamine (letter).. Clin Pharmacol Ther
2004; 76(5):509-510.
Montejo-Gonzalez AL, Liorca G, Izquierdo JA, et al: SSRI-induced sexual dysfunction: fluoxetine, paroxetine,
sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex
Marital Ther 1997; 23(3):176-194.
Montgomery SA: Novel selective serotonin reuptake inhibitors. Part 1. J Clin Psychiatry 1992; 53:107-112.
Moore MR & Hift RJ: Drugs in the acute porphyrias--toxicogenetic diseases. Cell Mol Biol (Noisy-le-grand) 1997;
43(1):89-94.
Mort JR, Aparasu RR, & Baer RK: Interaction between selective serotonin reuptake inhibitors and nonsteroidal
antiinflammatory drugs: review of the literature. Pharmacotherapy 2006; 26(9):1307-1313.
Mullin JM, Pandita-Gunawardena VR, & Whitehead AM: A double-blind comparison of fluvoxamine and dothiepin
in the treatment of major affective disorder. Br J Clin Pract 1988; 42:51-55.
Muly EC, McDonald W, Steffens D, et al: Serotonin syndrome produced by a combination of fluoxetine and lithium
(letter). Am J Psychiatry 1993; 150:1565.
Muly EC, McDonald W, Steffens D, et al: Serotonin syndrome produced by a combination of fluoxetine and lithium
(letter). Am J Psychiatry 1993a; 150:1565.
Mundo E, Bareggi SB, Pirola R, et al: Long-term pharmacotherapy of obsessive-compulsive disorder: a doubleblind controlled study. J Clin Psychopharmacol 1997; 17:4-10.
Munjack DJ: Sex and Drugs. Clin Toxicol 1979; 15:75.
Nafziger AN, Bertino JS Jr, Goss-Bley AI, et al: Incidence of sexual dysfunction in healthy volunteers on
fluvoxamine therapy. J Clin Psychiatry 1999; 60:187-190.
Nemeth A, Arato M, Treuer T, et al: Treatment of fluvoxamine-induced anorgasmia with a partial drug holiday. Am
J Psychiatry 1996; 153:1365-1366.
Neuvonen PJ, Pohjola-Sintonen S, Tacke U, et al: Five fatal cases of serotonin syndrome after moclobemidecitalopram or moclobemide-clomipramine overdoses (letter). Lancet 1993; 342:1419.
Neuvonen PJ, Pohjola-Sintonen S, Tacke U, et al: Five fatal cases of serotonin syndrome after moclobemide-
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 152
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
369.
370.
371.
372.
373.
374.
375.
376.
377.
378.
379.
380.
381.
382.
383.
384.
385.
386.
387.
388.
389.
390.
391.
392.
393.
394.
395.
396.
397.
398.
399.
400.
401.
402.
403.
404.
405.
406.
Filed 03/24/2010
Pageof153
of 160
Page 153
244
citalopram or moclobemide-clomipramine overdoses (letter). Lancet 1993a; 342:1419.
Newman RJ & Salerno HR: Sexual dysfunction due to methyldopa. Br Med J 1974; 4:106.
Niemi M, Backman JT, Neuvonen M, et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and
pharmacodynamics of glimepiride. Clin Pharmacol Ther 2001; 69(4):194-200.
Ninan PT, McElroy SL, Kane CP, et al: Placebo-controlled study of fluvoxamine in the treatment of patients with
compulsive buying. J Clin Psychopharmacol 2000; 20(3):362-366.
Nishikai M & Akiya K: Fluvoxamine therapy for fibromyalgia. J Rheumatol 2003; 30(5):1124-.
Nolen WA, van de Putte JJ, Dijken WA, et al: Treatment strategy in depression. Acta Psychiatr Scand 1988;
78:668-675.
Norton KR, Sireling LI, Bhat AV, et al: A double-blind comparison of fluvoxamine, imipramine and placebo in
depressed patients. J Affect Disord 1984; 7:297-308.
Noveske FG, Hahn KR, & Flynn RJ: Possible toxicity of combined fluoxetine and lithium (letter). Am J Psychiatry
1989; 146:1515.
Noveske FG, Hahn KR, & Flynn RJ: Possible toxicity of combined fluoxetine and lithium (letter). Am J Psychiatry
1989a; 146:1515.
Nurnberg HG, Lauriello J, Hensley PL, et al: Sildenafil for iatrogenic serotonergic antidepressant medicationinduced sexual dysfunction in 4 patients. J Clin Psychiatry 1999; 60(1):33-35.
O'Carroll RE, Moffoot APR, Ebmeier KP, et al: Effects of fluvoxamine treatment on cognitive functioning in the
alcoholic Korsakoff Syndrome. Psychopharmacol 1994; 116:85-88.
Ochs HR, Greenblatt DJ, Vergurg-Ochs B, et al: Chronic treatment with fluvoxamine, clovoxamine, and placebo:
interception with digoxin and effects on sleep and alertness. J Clin Pharmacol 1989; 29:91-95.
Ohman R & Spigset O: Serotonin syndrome induced by fluvoxamine-lithium interaction. Pharmacopsychiatry 1993;
26:263-264.
Ohman R & Spigset O: Serotonin syndrome induced by fluvoxamine-lithium interaction. Pharmacopsychiatry
1993a; 26:263-264.
Okada F & Okajima K: Abnormalities of thermoregulation induced by fluvoxamine (letter). J Clin Psychopharmacol
2001; 21(6):619-621.
Onesti G, Bock KD, Heimsoth U, et al: Clonidine: a new antihypertensive agent. Am J Cardiol 1971; 28:74.
Oswald P, Souery D, & Mendlewicz J: Fluvoxamine-induced hyperglycaemia in a diabetic patient with comorbid
depression. Int J Neuropsychopharmacol 2003; 6(1):85-87.
Ottevanger EA: The efficacy of fluvoxamine in patients with severe depression. Prog Neuropsychopharmacol Biol
Psychiatry 1994; 18:731-740.
Palmer JD & Nugent CA: Guanadrel sulfate: a postganglonic sympathetic inhibitor for the treatment of mild to
moderate hypertension. Pharmacotherapy 1983; 3:220.
Palop V, Jimenez MJ, Catalan C, et al: Acute dystonia associated with fluvoxamine-metoclopramide (letter). Ann
Pharmacother 1999; 33:382.
Papadopoulos C: Cardiovascular drugs and sexuality. A cardiologist's review. Arch Intern Med 1980; 140:1341.
Parameshwar MRC: Hair loss associated with fluvoxamine use (letter). Am J Psychiatry 1996; 153:581-582.
Parker G & Blennerhassett J: Withdrawal reactions associated with venlafaxine. Aust N Z J Psychiatry 1998; 32
(2):291-294.
Peck AW: Incidence of seizures during treatment of tricyclic antidepressant drugs and bupropion. J Clin Psychiatry
1983; 44:197-201.
Perez A & Ashford JJ: A double-blind, randomized comparison of fluvoxamine with mianserin in depressive illness.
Cur Med Res Opin 1990; 12:234-241.
Perna G, Bertani A, Gabriele A, et al: Modification of 35% carbon dioxide hypersensitivity across one week of
treatment with clomipramine and fluvoxamine: a double-blind, randomized, placebo-controlled study. J Clin
Psychopharmacol 1997; 17:173-178.
Perry HM: Treatment of mild hypertension: preliminary results of a two-year feasibility trial. Circ Res 1977;
40:1180.
Perucca E, Gatti G, & Spina E: Clinical Pharmacokinetics of fluvoxamine.. Clin Pharmacokinet 1994a; 27(3):17590.
Perucca E, Gatti G, & Spina E: Clinical pharmacokinetics of fluvoxamine. Clin Pharmacokinet 1994; 27:175-190.
Phanjoo AL, Wonnacott S, & Hodgson A: Double-blind comparative multicentre study of fluvoxamine and
mianserin in the treatment of major depressive episode in elderly people. Acta Psychiatr Scand 1991; 83:476-479.
Phillips KA, McElroy SL, Dwight MM, et al: Delusionality and response to open-label fluvoxamine in body
dysmorphic disorder. J Clin Psychiatry 2001; 62(2):87-91.
Phillips SD: A possible paroxetine withdrawal syndrome (letter). Am J Psychiatry 1995; 152:645-646.
Pillay VKG: Some side-effects of alpha-methyldopa. S Afr Med J 1976; 50:625.
Pitts NE: A clinical evaluation of prazosin, a new antihypertensive agent. Postgrad Med 1975; 58:117.
Porro V, Fiorenzoni S, Menga C, et al: Single-blind comparison of the efficacy of fluvoxamine versus placebo in
patients with depressive syndrome. Curr Ther Res 1988; 43:621-629.
Porsolt RD, Roux S, & Drieu K: Evaluation of a ginkgo biloba extract (EGb 761) in functional tests for monoamine
oxidase inhibition. Arzneim-Forsch/Drug Res 2000; 50:232-235.
Price LH, Goodman WK, Charney DS, et al: Treatment of severe obsessive-compulsive disorder with fluvoxamine.
Am J Psychiatry 1987; 144:1059-1061.
Product Information: AZILECT(R) oral tablets, rasagiline oral tablets. Teva Pharmaceuticals, Kfar Saba, Israel,
2006.
Product Information: Amerge(TM), naratriptan hydrochloride. GlaxoSmithKline, Research Triangle Park, NC, 2002.
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 153
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
407.
408.
409.
410.
411.
412.
413.
414.
415.
416.
417.
418.
419.
420.
421.
422.
423.
424.
425.
426.
427.
428.
429.
430.
431.
432.
433.
434.
435.
436.
437.
438.
439.
440.
441.
442.
443.
444.
445.
446.
447.
448.
449.
450.
451.
452.
453.
454.
455.
456.
457.
458.
459.
460.
Filed 03/24/2010
Pageof154
of 160
Page 154
244
Product Information: Axert(TM), almotriptan. Pharmacia Corporation, Chicago, IL, 2001.
Product Information: CELEXA (R) oral tablet, solution, citalopram hydrobromide oral tablet, solution. Forest
Pharmaceuticals Inc, St. Louis, MO, 2005.
Product Information: CELEXA(R) oral tablets, solution, citalopram hydrobromide oral tablets, solution. Forest
Pharmaceuticals,Inc, St.Louis, MO, 2008.
Product Information: CYMBALTA(R) delayed-release oral capsules, duloxetine hcl delayed-release oral capsules.
Eli Lilly and Company, Indianapolis, IN, 2008.
Product Information: Cafergot(R), ergotamine tartrate and caffeine. Novartis Phamaceuticals Corporation, East
Hanover, NJ, 2002.
Product Information: Celexa(R), citalopram hydrobromide. Forest Laboratories, Inc., St. Louis, MO, 2004.
Product Information: Cerebyx(R), fosphenytoin sodium injection. Parke-Davis, Division of Warner-Lambert, Morris
Plains, NJ, 1999.
Product Information: Clozaril(R), clozapine. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2002.
Product Information: Effexor XR(R) extended-release oral capsules, venlafaxine hydrochloride extended-release
oral capsules. Wyeth Pharmaceuticals, Inc., Philadelphia, PA, 2009.
Product Information: Effexor(R) oral tablets, venlafaxine hydrochloride oral tablets. Wyeth Pharmaceuticals Inc.,
Philadelphia, PA, 2009.
Product Information: Frova(R), Frovatriptan. Endo Pharmaceuticals Inc., Chadds Ford, PA, 2004.
Product Information: Furoxone(R), furazolidone. Roberts Pharmaceutical Corporation, Eatontown, New Jersey,
1999.
Product Information: Hismanal(R), astemizole. Janssen Pharmaceutica Inc., Titusville, NJ, 1998.
Product Information: Imitrex(R) Nasal Spray, sumatriptan nasal spray. GlaxoSmithKline, Research Triangle Park,
NC, 2003.
Product Information: Imitrex(R), sumatriptan. Glaxo Wellcome Inc., Research Triangle Park, NC, 1998.
Product Information: Imitrex(R), sumatriptan. Glaxo Wellcome Inc., Research Triangle Park, NC, 1998a.
Product Information: Imitrex(R), sumatriptan. GlaxoSmithKline, Research Triangle Park, NC, 2002.
Product Information: Inapsine(R), droperidol. Akorn Manufacturing Inc., Decatur, IL, 2002.
Product Information: LOTRONEX(R), alosetron hydrochloride. GlaxoSmithKline, Research Triangle Park, NC,
2005.
Product Information: LUVOX(R) CR extended-release oral capsules, fluvoxamine maleate extended-release oral
capsules. Jazz Pharmaceuticals,Inc, Palo Alto, CA, 2008.
Product Information: LUVOX(R) oral tablets, fluvoxamine maleate oral tablets. Jazz Pharmaceuticals Inc, Palo
Alto, CA, 2007.
Product Information: LUVOX(R) oral tablets, fluvoxamine maleate oral tablets. Jazz Pharmaceuticals Inc, Palo
Alto, CA, 2008.
Product Information: Lexapro(R) oral tablets, solution, escitalopram oxalate oral tablets, solution. Forest
Pharmaceuticals, Inc., St. Louis, MO, 2009.
Product Information: Lexapro(TM), escitalopram. Forest Pharmaceuticals, Inc., St. Louis, MO, 2003.
Product Information: Luvox(R), fluvoxamine maleate tablets. Solvay Pharmaceuticals, Inc., Marietta, GA, 2000.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997a.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997aa.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997ab.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997b.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997c.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997d.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997e.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997f.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997g.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997h.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997i.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997j.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997k.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997l.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997m.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997n.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997o.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997p.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997q.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997r.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997s.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997t.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997u.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997v.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997w.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997x.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997y.
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Inc., Marietta, GA, 1997z.
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 154
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
461.
462.
463.
464.
465.
466.
467.
468.
469.
470.
471.
472.
473.
474.
475.
476.
477.
478.
479.
480.
481.
482.
483.
484.
485.
486.
487.
488.
489.
490.
491.
492.
493.
494.
495.
496.
497.
498.
499.
500.
501.
502.
503.
Filed 03/24/2010
Pageof155
of 160
Page 155
244
Product Information: Luvox(R), fluvoxamine. Solvay Pharmaceuticals, Marietta, GA, 1998.
Product Information: Luvox. Solvay, US, 97.
Product Information: MERIDIA(R) oral capsules, sibutramine hcl monohydrate oral capsules. Abbott Laboratories,
North Chicago, IL, 2006.
Product Information: METADATE CD(R) extended-release oral capsules, methylphenidate hcl extended-release
oral capsules. UCB,Inc, Smyrna, GA, 2007.
Product Information: Marplan(R), isocarboxazid. Roche Laboratories Inc., Nutley, NJ, 1998.
Product Information: Maxalt(R), rizatriptan benzoate. Merck & Co., Inc., West Point, PA, 1998.
Product Information: Maxalt(R), rizatriptan benzoate. Merck & Co., Inc., West Point, PA, 1998a.
Product Information: Mellaril(R), thioridazine hydrochloride. Novartis Pharmaceuticals Corporation, East Hanover,
NJ, 2000.
Product Information: Mellaril(R), thioridazine hydrochloride. Novartis Pharmaceuticals Corporation, East Hanover,
NJ, 2000a.
Product Information: Meridia(R), sibutramine hydrochloride monohydrate. Knoll Pharmaceutical Company, Mount
Olive, NJ, 1997.
Product Information: Mexitil(R), mexiletine. Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, 2003.
Product Information: Nardil(R), phenelzine. Parke-Davis, Morris Plains, NJ, 1997.
Product Information: Naropin(TM), ropivacaine injection. Astra USA, Inc., Westborough, MA, 1996.
Product Information: Orlaam(R), levomethadyl. Roxane Laboratories, Inc., 2001.
Product Information: PAXIL CR(R) controlled release oral tablets, paroxetine hcl controlled release oral tablets.
GlaxoSmithKline, Research Triangle Park, NC, 2006.
Product Information: PAXIL(R) oral tablets, suspension, paroxetine hydrochloride oral tablets, suspension.
GlaxoSmithKline, Research Triangle Park, NC, 2008.
Product Information: PAXIL(R) tablets and oral suspension, paroxetine hydrochloride tablets and oral suspension.
GlaxoSmithKline, Research Triangle Park, NC, 2005.
Product Information: PLAVIX(R) oral tablet, clopidogrel bisulfate oral tablet. Bristol-Myers Squibb/Sanofi
Pharmaceuticals Partnership, Bridgewater, NJ, 2009.
Product Information: PRISTIQ(TM) oral extended-release tablets, desvenlafaxine oral extended-release tablets.
Wyeth Pharmaceuticals Inc, Philadelphia, PA, 2008.
Product Information: PROMACTA(R) oral tablets, eltrombopag oral tablets. Glaxo Smith Kline, Research Triangle
Park,, NC, 2008.
Product Information: PROZAC(R) delayed-release capsules, oral capsules, solution, fluoxetine delayed-release
capsules, oral capsules, solution. Eli Lilly and Company, Indianapolis, IN, 2009.
Product Information: PROZAC(R) oral capsules, delayed-release capsules, solution, fluoxetine oral capsules,
delayed-release capsules, solution. Eli Lilly and Company, Indianapolis, IN, 2008.
Product Information: Paxil CR(TM), paroxetine hydrochloride. GlaxoSmithKline, Research Triangle Park, NC,
2003.
Product Information: Paxil(R), paroxetine. GlaxoSmithKline, Research Triangle Park, NC, 2002.
Product Information: ProSom(TM), estazolam tablets. Abbott Laboratories, North Chicago, IL, USA, 2004.
Product Information: RAZADYNE(R) ER extended release oral capsules, oral tablets, oral solution, galantamine
hBr extended release oral capsules, oral tablets, oral solution. Ortho-McNeil Neurologics,Inc, Titusville, NJ, 2007.
Product Information: ROZEREM(R) oral tablets, ramelteon oral tablets. Takeda Pharmaceutical Company,
Lincolnshire, IL, 2008.
Product Information: Redux(R), dexfenfluramine hydrochloride. Wyeth Laboratories Inc, Lexington, MA, 1997.
Product Information: Relpax(R), eletriptan hydrobromide. Pfizer Inc., New York City, NY, 2003.
Product Information: SAVELLA(R) oral tablets, milnacipran HCL oral tablets. Forest Pharmaceuticals, St Louis,
MO, 2009.
Product Information: SERZONE(R) oral tablets, nefazodone hcl oral tablets. Bristol-Myers Squibb Company,
Princeton, NJ, 2005.
Product Information: TORADOL(R) oral tablets, ketorolac tromethamine oral tablets. Roche Laboratories Inc,
Nutley, NJ, 2007.
Product Information: TREANDA(R) IV injection, bendamustine hcl IV injection. Cephalon,Inc, Frazer, PA, 2008.
Product Information: Ultram(R), tramadol hydrochloride. Ortho-McNeil Pharmaceutical, Raritan, NJ, 2001.
Product Information: WELLBUTRIN(R) oral tablets, bupropion hydrochloride oral tablets. GlaxoSmithKline,
Greenville, NC, 2008.
Product Information: ZOLOFT(R) concentrate, oral tablets, sertraline hcl concentrate, oral tablets. Roerig, Division
of Pfizer Inc, New York, NY, 2009.
Product Information: ZYVOX(R) IV injection, oral tablets, oral suspension, linezolid IV injection, oral tablets, oral
suspension. Pharmacia & Upjohn Company, New York, NY, 2008.
Product Information: Zanaflex (R) Tablets, tizanidine hydrochloride tablets. Acorda Therapeutics, Inc., Hawthorne,
New York, 2004.
Product Information: Zomig(R), zolmitriptan. AstraZeneca Pharmaceuticals, Wilmington, DE, 2002.
Product Information: Zomig(TM), zolmitriptan. Zeneca Pharmaceuticals, Wilmington, DE, 1997.
Product Information: Zyprexa(R), olanzapine. Eli Lilly and Company, Indianapolis, IN, 1999.
Product Information: fluvoxamine maleate oral tablets, fluvoxamine maleate oral tablets. Eon Labs,Inc., Laurelton,
NY, 2005.
Product Information: fluvoxamine maleate oral tablets, fluvoxamine maleate oral tablets. Jazz Pharmaceuticals
Inc, Palo Alto, CA, 2009.
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 155
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
504.
505.
506.
507.
508.
509.
510.
511.
512.
513.
514.
515.
516.
517.
518.
519.
520.
521.
522.
523.
524.
525.
526.
527.
528.
529.
530.
531.
532.
533.
534.
535.
536.
537.
Filed 03/24/2010
Pageof156
of 160
Page 156
244
Product Information: tapentadol immediate release oral tablets, tapentadol immediate release oral tablets. OrthoMcNeil-Janssen Pharmaceuticals Inc, Raritan, NJ, 2008.
Product Information: tizanidine hcl tablets, tizanidine hcl tablets. Corepharma,LLC, Middlesex, NJ, 2006.
Psychiatric Disease Advisory Panel Meeting.. ., 11/7/94.
Rahman MK, Savla NC, Kellett JM, et al: A double-blind, randomized comparison of fluvoxamine with dothiepin in
the treatment of depression in elderly patients. Br J Clin Pract 1991; 45:255-258.
Ramassamy C, Christen Y, Clostre F, et al: The Ginkgo biloba extract, EGb761, increases synaptosomal uptake
of 5-hydroxytryptamine: in-vitro and ex-vivo studies. J Pharm Pharmacol 1992; 44:943-945.
Rapaport M, Coccaro E, Sheline Y, et al: A comparison of fluvoxamine and fluoxetine in the treatment of major
depression. J Clin Psychopharmacol 1996; 16:373-378.
Rasmussen BB, Nielsen TL, & Brosen K: Fluvoxamine is a potent inhibitor of the metabolism of caffeine in vitro.
Pharmacol Toxicol 1998; 83:240-245.
Rasmussen BB, Nielsen TL, & Brosen K: Fluvoxamine is a potent inhibitor of the metabolism of caffeine in vitro.
Pharmacol Toxicol 1998a; 83:240-245.
Rasmussen SA & Eisen JL: Treatment strategies for chronic and refractory obsessive-compulsive disorder. J Clin
Psychiatry; 58(suppl 13)9-13, 1997.
Ravizza L, Berzega G, Bellino S, et al: Drug treatment of obsessive-compulsive disorder (OCD): long-term trial
with clomipramine and selective serotonin re-uptake inhibitors (SSRIs). Psychopharmacol Bull 1996; 32:167-173.
Ray WA, Meredith S, Thapa PB, et al: Cyclic antidepressants and the risk of sudden cardiac death. Clin
Pharmacol Ther 2004; 75(3):234-241.
Reeves RR, Mack JE, & Beddingfield JJ: Shock-like sensations during venlafaxine withdrawal. Pharmacotherapy
2003; 23(5):678-681.
Remick RA, Reesal R, Oakander M, et al: Comparison of fluvoxamine and amitriptyline in depressed outpatients.
Curr Therap Res 1994; 55:243-250.
Richards JB, Papaioannou A, Adachi JD, et al: Effect of selective serotonin reuptake inhibitors on the risk of
fracture. Arch Intern Med 2007; 167(2):188-194.
Richelson E & Nelson A: Antagonism by antidepressants of neurotransmitter receptors of normal human brain in
vitro. J Pharmacol Exp Therap 1984; 230:94-102.
Riddiough MA: Preventing, detecting and managing adverse reactions of antihypertensive agents in the ambulant
patient with essential hypertension. Am J Hosp Pharm 1977; 39:465.
Riddle MA: Fluvoxamine in the treatment of OCD in children and adolescents: a multicenter, double-blind,
placebo-controlled trial (abstract NR197). APA Meeting, May 7, 1996, May 7, 1996.
Robinson JF & Doogan DP: A placebo controlled study of the cardiovascular effects of fluvoxamine and
clovoxamine in human volunteers. Br J Clin Pharmacol 1982; 14:805-808.
Rocco PL & De Leo D: Fluvoxamine-induced acute exacerbation in residual schizophrenia. Pharmacopsychiatry
1992; 25:245.
Roos JC: Cardiac effects of antidepressant drugs: a comparison of the tricyclic antidepressants and fluvoxamine.
Br J Clin Pharmacol 1983; 15(suppl 3):439S-445S.
Roos JC: Cardiac effects of antidepressant drugs: a comparison of the tricyclic antidepressants and fluvoxamine.
Br J Clin Pharmacol 1983a; 15(suppl 3):439S-445S.
Rose LE, Underwood RH, Newmark SR, et al: Pathophysiology of spironolactone-induced gynecomastia. Ann
Intern Med 1977; 87:398.
Rosen RC, Lane RM, & Menza M: Effects of SSRIs on sexual function: a critical review. J Clin Psychopharmacol
1999; 19(1):67-85.
Roth D, Mattes J, Sheehan KH, et al: A double-blind comparison of fluvoxamine, desipramine and placebo in
outpatients with depression. Prog Neuropsychopharmacol Biol Psychiatry 1990; 14:929-939.
Rothschild AJ: New directions in the treatment of antidepressant-induced sexual dysfunction. Clin Ther 2000; 22
(Suppl A):A42-A61.
Salama AA & Shafey M: A case of severe lithium toxicity induced by combined fluoxetine and lithium carbonate
(letter). Am J Psychiatry 1989; 146:278.
Salama AA & Shafey M: A case of severe lithium toxicity induced by combined fluoxetine and lithium carbonate
(letter). Am J Psychiatry 1989a; 146:278.
Saletu B, Grunberger J, & Rajna P: Pharmaco-EEG profiles of antidepressants: pharmacodynamic studies with
fluvoxamine. Br J Clin Pharmacol 1983; 15:369S-384S.
Saletu B, Grunberger J, Rajna P, et al: Clovoxamine and fluvoxamine-2 biogenic amine re-uptake inhibiting
antidepressants: quantitative EEG, psychometric and pharmacokinetic studies in man. J Neural Transm 1980;
49:63-86.
Saletu B, Grunberger J, Rajna P, et al: Clovoxamine and fluvoxamine-2 biogenic amine re-uptake inhibiting
antidepressants: quantitative EEG, psychometric and pharmacokinetic studies in man. J Neural Transm 1980a;
49:63-86.
Sandison RA, Whitelaw E, & Currie JDC: Clinical trials with Mellaril (TP21) in the treatment of schizophrenia. J
Ment Sci 1960; 106:732.
Sauer WH, Berlin JA, & Kimmel SE: Selective serotonin reuptake inhibitors and myocardial infarction. Circulation
2001; 104:1894-1898.
Schachter M & Parkes JD: Fluvoxamine and clomipramine in the treatment of cataplexy. J Neurol Neurosurg
Psychiatry 1980; 43:171-174.
Schalekamp T, Klungel OH, Souverein PC, et al: Increased bleeding risk with concurrent use of selective
serotonin reuptake inhibitors and coumarins. Arch Intern Med 2008; 168(2):180-185.
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 156
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
538.
539.
540.
541.
542.
543.
544.
545.
546.
547.
548.
549.
550.
551.
552.
553.
554.
555.
556.
557.
558.
559.
560.
561.
562.
563.
564.
565.
566.
567.
568.
569.
570.
571.
572.
573.
574.
Filed 03/24/2010
Pageof157
of 160
Page 157
244
Schenck CH & Mahowald MW: Potential hazard of serotonin syndrome associated with dexfenfluramine
hydrochloride (Redux) (letter). JAMA 1996; 276:1220-1221.
Schenck CH & Mahowald MW: Potential hazard of serotonin syndrome associated with dexfenfluramine
hydrochloride (Redux) (letter). JAMA 1996a; 276:1220-1221.
Schmider J, Greenblatt DJ, von Moltke LL, et al: Inhibition of CYP2C9 by selective serotonin reuptake inhibitors in
vitro: studies of phenytoin p-hydroxylation. Br J Clin Pharmacol 1997; 44:495-498.
Schmider J, Greenblatt DJ, von Moltke LL, et al: Inhibition of CYP2C9 by selective serotonin reuptake inhibitors in
vitro: studies of phenytoin p-hydroxylation. Br J Clin Pharmacol 1997a; 44:495-498.
Segraves RT: Antidepressant-induced sexual dysfunction. J Clin Psychiatry 1998; 59(suppl 4):48-54.
Semmens JP & Semmens FJ: Inadequate vaginal lubrication. Med Asp Hum Sex 1978; 12:58.
Servant D, Bailly D, & Parquet PHJ: Fluvoxamine in the treatment of panic disorder with obsessive-compulsive
symptoms. Am J Psychiatry 1988; 145:1174-1175.
Sesardic D, Boobis AR, Murray BP, et al: Furafylline is a potent and selective inhibitor of cytochrome P450IA2 in
man. Br J Clin Pharmacol 1990; 29:651-663.
Sesardic D, Boobis AR, Murray BP, et al: Furafylline is a potent and selective inhibitor of cytochrome P450IA2 in
man. Br J Clin Pharmacol 1990a; 29:651-663.
Shen WW & Mallya AR: Psychotropic-induced sexual inhibition. Am J Psychiatry 1983; 140:514.
Shen WW & Sata LS: Neuropharmacology of the male sexual function. J Clin Psychopharmacol 1983; 3:265.
Shen WW, Urosevich Z, & Clayton DO: Sildenafil in the treatment of female sexual dysfunction induced by
selective serotonin reuptake inhibitors. J Reprod Med 1999; 44:535-542.
Silver H & Shmugliakov N: Augmentation with fluvoxamine but not maprotiline improves negative symptoms in
treated schizophrenia: evidence for a specific serotonergic effect from a double-blind study. J Clin
Psychopharmacol 1998; 18:208-211.
Sim FH & Massabki RA: A single dose of fluvoxamine associated with an acute psychotic reaction (letter). Can J
Psychiatry 2000; 45(8):762.
Simpson WT: Nature and incidence of unwanted effects with atenolol. Postgrad Med J 1977; 53:162.
Singer A, Wonnemann M, & Muller WE: Hyperforin, a major antidepressant constituent of St. John's wort, inhibits
serotonin uptake by elevating free intracellular Na+. J Pharmacol Exp Ther 1999; 290(3):1361-1368.
Skop BP & Brown TM: Potential vascular and bleeding complications of treatment with selective serotonin
reuptake inhibitors. Psychosomatics 1996; 37(1):12-16.
Slag MF, Morley JE, Elson MK, et al: Impotence in medical clinic outpatients. JAMA 1983; 249:1736.
Sloley BD, Urichik LJ, Morley P, et al: Identification of kaempferol as a monoamine oxidase inhibitor and potential
neuroprotectant in extracts of ginkgo biloba leaves. J Pharm Pharmacol 2000; 52:451-459.
Smith DE, Moser C, Wesson DR, et al: A clinical guide to the diagnosis and treatment of heroin-related sexual
dysfunction. J Psychoactive Drugs 1982; 14:91.
Sonawalla SB, Spillmann MK, Kolsy AR, et al: Efficacy of fluvoxamine in the treatment of major depression with
comorbid anxiety disorders. J Clin Psychiatry 1999; 60(9):580-583.
Spark RF & Melby JC: Aldosteronism in hypertension: the spironolactone response test. Ann Intern Med 1968;
69:685.
Sperber AD: Toxic interaction between fluvoxamine and sustained release theophylline in an 11-year-old boy.
Drug Saf 1991; 6:460-462.
Sperber AD: Toxic interaction between fluvoxamine and sustained release theophylline in an 11-year-old boy.
Drug Saf 1991a; 6:460-462.
Spiegel DA, Saeed A, & Bruce TJ: An open trial of fluvoxamine therapy for panic disorder complicated by
depression. J Clin Psychiatry 1996; 57(suppl 8):37-41.
Spina E, Avenoso A, Pollicino AM, et al: Carbamazepine coadministration with fluoxetine and fluvoxamine. Ther
Drug Monit 1993d; 15:247-250.
Spina E, Avenoso A, Pollicino AM, et al: Carbamazepine coadministration with fluoxetine and fluvoxamine. Ther
Drug Monit 1993e; 15:247-250.
Spina E, Campo GM, Avenoso A, et al: Interaction between fluvoxamine and imipramine/desipramine in four
patients. Ther Drug Monit 1992; 14:194-196.
Spina E, Campo GM, Avenoso A, et al: Interaction between fluvoxamine and imipramine/desipramine in four
patients. Ther Drug Monit 1992a; 14:194-196.
Spina E, Campo GM, Avenoso A, et al: Interaction between fluvoxamine and imipramine/desipramine in four
patients. Ther Drug Monit 1992b; 14:194-196.
Spina E, Campo GM, Avenoso A, et al: Interaction between fluvoxamine and imipramine/desipramine in four
patients. Ther Drug Monit 1992c; 14:194-196.
Spina E, Pollicino AM, Avenoso A, et al: Effect of fluvoxamine on the pharmacokinetics of imipramine and
desipramine in healthy subjects. Ther Drug Monit 1993; 15:243-246.
Spina E, Pollicino AM, Avenoso A, et al: Effect of fluvoxamine on the pharmacokinetics of imipramine and
desipramine in healthy subjects. Ther Drug Monit 1993a; 15:243-246.
Spina E, Pollicino AM, Avenoso A, et al: Effect of fluvoxamine on the pharmacokinetics of imipramine and
desipramine in healthy subjects. Ther Drug Monit 1993c; 15:243-246.
Spina E, Pollicino AM, Avenoso A, et al: Fluvoxamine-induced alterations in plasma concentrations of imipramine
and desipramine in depressed patients. Int J Clin Pharmacol Res 1993a; 13:167-171.
Spina E, Pollicino AM, Avenoso A, et al: Fluvoxamine-induced alterations in plasma concentrations of imipramine
and desipramine in depressed patients. Int J Clin Pharmacol Res 1993aa; 13:167-171.
Spina E, Pollicino AM, Avenoso A, et al: Fluvoxamine-induced alterations in plasma concentrations of imipramine
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 157
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
575.
576.
577.
578.
579.
580.
581.
582.
583.
584.
585.
586.
587.
588.
589.
590.
591.
592.
593.
594.
595.
596.
597.
598.
599.
600.
601.
602.
603.
604.
605.
606.
607.
608.
609.
610.
611.
612.
613.
614.
615.
616.
617.
Filed 03/24/2010
Pageof158
of 160
Page 158
244
and desipramine in depressed patients. Int J Clin Pharmacol Res 1993ab; 13:167-171.
Spina E, Pollicino AM, Avenoso A, et al: Fluvoxamine-induced alterations in plasma concentrations of imipramine
and desipramine in depressed patients. Int J Clin Pharmacol Res 1993ac; 13:167-171.
Spina E, Pollicino AM, Avenoso A, et al: Fluvoxamine-induced alterations in plasma concentrations of imipramine
and desipramine in depressed patients. Int J Clin Pharmacol Res 1993b; 13:167-171.
Spinella M & Eaton LA: Hypomania induced by herbal and pharmaceutical psychotropic medicines following mild
traumatic brain injury. Brain Injury 2002; 16(4):359-367.
Spinella M & Eaton LA: Hypomania induced by herbal and pharmaceutical psychotropic medicines following mild
traumatic brain injury. Brain Injury 2002a; 16(4):359-367.
Spinella M & Eaton LA: Hypomania induced by herbal and pharmaceutical psychotropic medicines following mild
traumatic brain injury. Brain Injury 2002b; 16(4):359-367.
Spinella M & Eaton LA: Hypomania induced by herbal and pharmaceutical psychotropic medicines following mild
traumatic brain injury. Brain Injury 2002c; 16(4):359-367.
Spinler SA: New concepts in heparin-induced thrombocytopenia: diagnosis and management. J Thromb
Thrombolysis 2006; 21(1):17-21.
Stanley MA, Breckenridge JK, Swann AC, et al: Fluvoxamine treatment of trichotillomania. J Clin
Psychopharmacol 1997; 17:278-283.
Stapleton JM, Eckardt MJ, Martin P, et al: Treatment of alcoholic organic brain syndrome with the serotonin
reuptake inhibitor fluvoxamine: a preliminary study. Adv Alcohol Subst Abuse 1988; 7:47-51.
Stein DJ, Westenberg HG, Yang H, et al: Fluvoxamine CR in the long-term treatment of social anxiety disorder:
the 12- to 24-week extension phase of a multicentre, randomized, placebo-controlled trial. Int J
Neuropsychopharmacol 2003; 6(4):317-323.
Stein JJ & Martin DC: Priapism. Urology 1974; 3:8.
Stein MB, Fyer AJ, Davidson JRT, et al: Fluvoxamine treatment of social phobia (social anxiety disorder): a
double-blind, placebo-controlled study. Am J Psychiatry 1999; 156:756-760.
Steiner J, Cassar J, Mashiterk, et al: Effects of methyldopa on prolactin and growth hormone. Br Med J 1976;
1:1186.
Sternbach H: The serotonin syndrome. Am J Psychiatry 1991; 148:705-713.
Sternbach H: The serotonin syndrome. Am J Psychiatry 1991a; 148:705-713.
Sternbach H: The serotonin syndrome. Am J Psychiatry 1991b; 148:705-713.
Sternbach H: The serotonin syndrome. Am J Psychiatry 1991c; 148:705-713.
Sternbach H: The serotonin syndrome. Am J Psychiatry 1991d; 148:705-713.
Sternbach H: The serotonin syndrome. Am J Psychiatry 1991e; 148:705-713.
Sternbach H: The serotonin syndrome. Am J Psychiatry 1991f; 148:705-713.
Sternbach H: The serotonin syndrome. Am J Psychiatry 1991g; 148:705-713.
Sternbach H: The serotonin syndrome. Am J Psychiatry 1991h; 148:705-713.
Sternbach H: The serotonin syndrome. Am J Psychiatry 1991i; 148:705-713.
Sternbach H: The serotonin syndrome. Am J Psychiatry 1991j; 148:705-713.
Sternbach H: The serotonin syndrome. Am J Psychiatry 1991k; 148:705-713.
Sternbach H: The serotonin syndrome. Am J Psychiatry 1991l; 148:705-713.
Sternbach H: The serotonin syndrome. Am J Psychiatry 1991m; 148:705-713.
Stevenson JG & Umstead GS: Sexual dysfunction due to antihypertensive agents. Drug Intell Clin Pharm 1984;
18:113.
Stiskal JA, Kulin N, Koren G, et al: Neonatal paroxetine withdrawal syndrome. Arch Dis Child Fetal Neonatal Ed
2001; 84:F134-F135.
Stoll AL, Cole JO, & Lukas SE: A case of mania as a result of fluoxetine-marijuana interaction. J Clin Psychiatry
1991; 52(6):280-281.
Stoll AL, Cole JO, & Lukas SE: A case of mania as a result of fluoxetine-marijuana interaction. J Clin Psychiatry
1991a; 52(6):280-281.
Stressman J & Ben-Ishay D: Chlorthalidone-induced impotence. Br Med J 1980; 281:714.
Suchowersky O & de Vries JD: Interaction of fluoxetine and selegiline (letter). Can J Psychiatry 1990; 35:571-572.
Suchowersky O & de Vries JD: Interaction of fluoxetine and selegiline (letter). Can J Psychiatry 1990a; 35:571572.
Suchowersky O & de Vries JD: Interaction of fluoxetine and selegiline (letter). Can J Psychiatry 1990b; 35:571572.
Suchowersky O & de Vries JD: Interaction of fluoxetine and selegiline (letter). Can J Psychiatry 1990c; 35:571572.
Suchowersky O & de Vries JD: Interaction of fluoxetine and selegiline (letter). Can J Psychiatry 1990d; 35:571572.
Suchowersky O & de Vries JD: Interaction of fluoxetine and selegiline (letter). Can J Psychiatry 1990e; 35:571572.
Suchowersky O & de Vries JD: Interaction of fluoxetine and selegiline (letter). Can J Psychiatry 1990f; 35:571-572.
Suchowersky O & de Vries JD: Interaction of fluoxetine and selegiline (letter). Can J Psychiatry 1990g; 35:571572.
Suchowersky O & de Vries JD: Interaction of fluoxetine and selegiline (letter). Can J Psychiatry 1990h; 35:571572.
Suchowersky O & de Vries JD: Interaction of fluoxetine and selegiline (letter). Can J Psychiatry 1990i; 35:571-572.
Suchowersky O & de Vries JD: Interaction of fluoxetine and selegiline (letter). Can J Psychiatry 1990j; 35:571-572.
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 158
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
618.
619.
620.
621.
622.
623.
624.
625.
626.
627.
628.
629.
630.
631.
632.
633.
634.
635.
636.
637.
638.
639.
640.
641.
642.
643.
644.
645.
646.
647.
648.
649.
650.
651.
652.
653.
654.
Filed 03/24/2010
Pageof159
of 160
Page 159
244
Suchowersky O & de Vries JD: Interaction of fluoxetine and selegiline (letter). Can J Psychiatry 1990k; 35:571572.
Suchowersky O & de Vries JD: Interaction of fluoxetine and selegiline (letter). Can J Psychiatry 1990l; 35:571-572.
Suchowersky O & de Vries JD: Interaction of fluoxetine and selegiline (letter). Can J Psychiatry 1990m; 35:571572.
Suchowersky O & de Vries JD: Interaction of fluoxetine and selegiline (letter). Can J Psychiatry 1990n; 35:571572.
Suchowersky O & de Vries JD: Interaction of fluoxetine and selegiline (letter). Can J Psychiatry 1990o; 35:571572.
Suchowersky O & de Vries JD: Interaction of fluoxetine and selegiline (letter). Can J Psychiatry 1990p; 35:571572.
Suchowersky O & de Vries JD: Interaction of fluoxetine and selegiline (letter). Can J Psychiatry 1990q; 35:571572.
Suchowersky O & de Vries JD: Interaction of fluoxetine and selegiline (letter). Can J Psychiatry 1990r; 35:571-572.
Suchowersky O & de Vries JD: Interaction of fluoxetine and selegiline (letter). Can J Psychiatry 1990s; 35:571572.
Tamam L & Ozpoyraz N: Selective serotonin reuptake inhibitor discontinuation syndrome: a review. Adv Ther
2002; 19(1):17-26.
Tasini M: Complex partial seizures in a patient receiving trazodone. J Clin Psychiatry 1986; 47:318-319.
Teilmann Larsen J, Lindal Hansen L, Spigset O, et al: Fluvoxamine is a potent inhibitor of tacrine metabolism in
vivo. Eur J Clin Pharmacol 1999; 55:375-382.
Teilmann Larsen J, Lindal Hansen L, Spigset O, et al: Fluvoxamine is a potent inhibitor of tacrine metabolism in
vivo. Eur J Clin Pharmacol 1999a; 55:375-382.
Thiede HM & Walper A: Inhibition of MAO and COMT by hypericum extracts and hypericin. J Geriatr Psychiatry
Neurol 1994; 7(Suppl 1):S54-S56.
Tielens JAE: Vitamin C for paroxetine- and fluvoxamine-associated bleeding. Am J Psychiatry 1997; 153:883-884.
Tourjman S & Fontaine R: Fluvoxamine can induce confusion in the elderly [letter].. J Clin Psychopharmacol 1992;
12(4):293.
Trappler B & Vinuela LM: Fluvoxamine for sterotypic behavior in patients with dementia. Ann Pharmacother 1997;
31:578-581.
Turkington D, Grant JBF, Ferrier IN, et al: A randomized controlled trial of fluvoxamine in prostatodynia, a male
somatoform pain disorder. J Clin Psychiatry 2002; 63:778-781.
US Food and Drug Administration: 5-Hydroxytryptamine Receptor Agonists (Triptans) Selective Serotonin
Reuptake Inhibitors (SSRIs) Selective Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) Serotonin
Syndrome. US Food and Drug Administration. Rockville, MDAvailable from URL:
http://www.fda.gov/medwatch/safety/2006/safety06.htm#Triptans.
Van Thiel DH & Lester R: Sex and alcohol. N Engl J Med 1974; 291:251.
Van Thiel DH & Lester R: Sex and alcohol: a second peek. N Engl J Med 1976; 295:835.
Van Thiel DH: Testicular atrophy and other endocrine changes in alcoholic men. Med Asp Human Sexuality 1976;
10:153.
Vasquez JM, Ellegova MS, Nazian SJ, et al: Effect of hyperprolactinemia on pituitary sensitivity to luteinizing
hormone-releasing hormone following manipulation of sex steroids. Fertil Steril 1980; 33:543.
Vella JP & Sayegh MH: Interactions between cyclosporine and newer antidepressant medications. Am J Kidney
Dis 1998; 31:320-323.
Vella JP & Sayegh MH: Interactions between cyclosporine and newer antidepressant medications. Am J Kidney
Dis 1998a; 31:320-323.
Vinarova E, Uhlif O, Stika L, et al: Side effects of lithium administration. Activ Nerv Sup (Praha) 1972; 14:105.
Von Bahr C, Ursing C, Yasui N, et al: Fluvoxamine but not citalopram increases serum melatonin in healthy
subjects - an indication that cytochrome P450 CYP1A2 and CYP2C19 hydroxylate melatonin. Eur J Clin
Pharmacol 2000; 56(2):123-127.
Vries MH, Raghoebar M, Mathlener IS, et al: Single and multiple oral dose fluvoxamine kinetics in young and
elderly subjects.. Ther Drug Monit 1992; 14(6):493-8.
Wagner W, Zaborny BA, & Gray TE: Fluvoxamine: a review of its safety profile in world-wide studies.. Int Clin
Psychopharmacol 1994; 9:223-7.
Waksman JC, Heard K, Jolliff H, et al: Serotonin syndrome associated with the use of St. John's Wort (Hypericum
perforatum) and paroxetine (abstract). Clin Toxicol 2000; 38(5):521.
Waksman JC, Heard K, Jolliff H, et al: Serotonin syndrome associated with the use of St. John's Wort (Hypericum
perforatum) and paroxetine (abstract). Clin Toxicol 2000a; 38(5):521.
Wallerstedt SM, Gleerup H, Sundstrom A, et al: Risk of clinically relevant bleeding in warfarin-treated patientsinfluence of SSRI treatment. Pharmacoepidemiol Drug Saf 2009; 18(5):412-416.
Wartman SA: Sexual side effects of antihypertensive drugs. Treatment strategies and structures. Postgrad Med
1983; 73:133.
Wedin GP: Relative toxicity of cyclic antidepressants. Ann Emerg Med 1986; 15:797-804.
Westenberg HG, Stein DJ, Yang H, et al: A double-blind placebo- controlled study of controlled release
fluvoxamine for the treatment of generalized social anxiety disorder. J Clin Psychopharmacol 2004; 24(1):49-55.
Westenberg HG, den Boer JA, & Kahn RS: Psychopharmacology of anxiety disorders: on the role of serotonin in
the treatment of anxiety states and phobic disorders. Psychopharm Bull 1987; 23:145-149.
Wetzel H, Anghelescu I, Szegedi A, et al: Pharmacokinetic interactions of clozapine with selective serotonin
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 159
7/1/2009
MICROMEDEX®
Healthcare SeriesDocument
: Document78-27
Case 3:09-cv-00080-TMB
655.
656.
657.
658.
659.
660.
661.
662.
663.
664.
665.
666.
667.
668.
669.
670.
671.
672.
673.
674.
675.
676.
677.
678.
679.
680.
681.
682.
683.
684.
Filed 03/24/2010
Pageof160
of 160
Page 160
244
reuptake inhibitors: differential effects of fluvoxamine and paroxetine in a prospective study. J Clin
Psychopharmacol 1998; 18:2-9.
Wetzel H, Anghelescu I, Szegedi A, et al: Pharmacokinetic interactions of clozapine with selective serotonin
reuptake inhibitors: differential effects of fluvoxamine and paroxetine in a prospective study. J Clin
Psychopharmacol 1998a; 18:2-9.
White HL, Scates PW, & Cooper BR: Extracts of ginkgo biloba leaves inhibit monoamine oxidase. Life Sci 1996;
58(16):1315-1321.
Wijkstra J, Lijmer J, Balk F, et al: Pharmacological treatment for psychotic depression. Cochrane Database Syst
Rev 2005; (4):CD004044.
Wilde MI, Plosker GL, & Benfield P: Fluvoxamine: an updated review of its pharmacology, and therapeutic use in
depressive illness.. Drugs 1993a; 46(5):895-924.
Wilde MI, Plosker GL, & Benfield P: Fluvoxamine: an updated review of its pharmacology, and therapeutic use in
depressive illness.. Drugs 1993; 46(5):895-924.
Wilner KD, Lazar JD, Von Deutsch DA, et al: The effects of sertraline on steady-state lithium levels and renal
clearance of lithium. Biol Psychiatry 1991; 29:354S.
Wilson WH, Higano H, Papadatos Y, et al: A double-blind placebo-controlled study to compare the autonomic
effects of fluvoxamine with those of amitriptyline and doxepin in healthy volunteers. Br J Clin Pharmacol 1983;
15:385S-392S.
Witton K: Sexual dysfunction secondary to mellaril. Dis Nerv Syst 1962; 23:175.
Wolfe RM: Antidepressant withdrawal reactions. Am Fam Physician 1997; 56:455-462.
Wolkenstein P, Revuz J, Diehl JL, et al: Toxic epidermal necrolysis after fluvoxamine. Lancet 1993; 342:304-305.
Woo MH & Smythe MA: Association of SIADH with selective serotonin reuptake inhibitors. Ann Pharmacother
1997; 31:108-110.
Woodrum ST & Brown CS: Management of SSRI-induced sexual dysfunction. Ann Pharmacother 1998; 32
(11):1209-1215.
Wright S, Dawling S, & Ashford JJ: Excretion of fluvoxamine in breast milk [letter].. Br J Clin Pharmacol 1991;
31:209.
Wroblewski BA: The incidence of seizures during tricyclic antidepressant drug treatment in a brain-injured
population. J Clin Psychopharmacol 1990; 10:124-128.
Yap KB & Low ST: Interaction of fluvoxamine with warfarin in an elderly woman. Singapore Med J 1999; 40:480482.
Yendt ER, Guay GF, & Garcia DA: The use of thiazides in the prevention of renal calculi. Can Med Assoc J 1970;
102:614.
Ylikahri R, Huttunen M, Harkunen M, et al: Low plasma testosterone values in men during hangover. J Steroid
Biochem 1974; 5:655.
Zajecka J, Tracy KA, & Mitchell S: Discontinuation symptoms after treatment with serotonin reuptake inhibitors: a
literature review. J Clin Psychiatry 1997; 58:291-297.
Zarren HS & Black PM: Unilateral gynecomastia and impotence during low-dose spironolactone administration in
men. Milit Med 1975; 140:417.
Ziere G, Dieleman JP, vanderCammen TJ, et al: Selective serotonin reuptake inhibiting antidepressants are
associated with an increased risk of nonvertebral fractures. J Clin Psychopharmacol 2008; 28(4):411-417.
Zohar J, Kaplan Z, & Benjamin J: Compulsive exhibitionism successfully treated with fluvoxamine: a controlled
case study. J Clin Psychiatry 1994; 55(3):86-88.
de Jong J, Hoogenboom B, van Troostwijk L, et al: Interaction of olanzapine with fluvoxamine.
Psychopharmacology 2001; 155:219-220.
deAbajo FJ, Montero D, Rodriguez LA, et al: Antidepressants and risk of upper gastrointestinal bleeding. Basic
Clin Pharmacol Toxicol 2006; 98(3):304-310.
deAbajo FJ, Rodriguez LA, & et al: Association between selective serotonin reuptake inhibitors and upper
gastrointestinal bleeding: population based case-control study. BMJ 1999; 319(7217):1106-1109.
van Harten J, Duchier J, Devissaguet J-P, et al: Pharmacokinetics of fluvoxamine maleate in patients with liver
cirrhosis after single-dose oral administration.. Clin Pharmacokinet 1993; 24(2):177-82.
van Harten J, Duchier J, Devissaguet JP, et al: Pharmacokinetics of fluvoxamine maleate in patients with liver
cirrhosis after single-dose oral administration. Clin Pharmacokinet 1993a; 24:177-182.
van Harten J: Clinical pharmacokinetics of selective serotonin reuptake inhibitors. Clin Pharmacokinet 1993;
24:203-220.
van Harten J: Overview of the pharmacokinetics of fluvoxamine.. Clin Pharmacokinet 1995; 29 Suppl 1:1-9.
van Noorden MS, Vergouwen AC, & Koerselman GF: Delirium during withdrawal of venlafaxine. Ned Tijdschr
Geneeskd 2002; 146(26):1236- 1237.
van den Brekel AM & Harrington L: Toxic effects of theophylline caused by fluvoxamine. Can Med Assoc J 1994;
151:1289-1290.
Last Modified: June 23, 2009
© 1974- 2009 Thomson Reuters. All rights reserved.
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
Exhibit E.17, page 160
7/1/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 1 of 84
Page 161 of 244
DRUGDEX® Evaluations
THIORIDAZINE
0.0 Overview
1) Class
a) This drug is a member of the following class(es):
Antipsychotic
Phenothiazine
Piperidine
2) Dosing Information
a) Thioridazine Hydrochloride
1) Adult
a) Schizophrenia, Refractory
1) initial, 50 to 100 mg ORALLY 3 times a day; may increase gradually to a MAX of 800 mg/day in 2 to
4 divided doses (Prod Info Mellaril(R), 2000)
2) maintenance, once effective control of symptoms achieved, may gradually reduce dose to determine
the minimum maintenance dose (range from 200 to 800 mg/day in 2 to 4 divided doses) (Prod Info
Mellaril(R), 2000)
2) Pediatric
a) Safety and effectiveness not established in children under 2 years of age
1) Schizophrenia, Refractory
a) initial, 0.5 mg/kg/day in divided doses; may increase gradually to a MAX of 3 mg/kg/day (Prod
Info Mellaril(R), 2000)
3) Contraindications
a) Thioridazine Hydrochloride
1) abnormal serum potassium concentration
2) central nervous system (CNS) depression, coma, or drug-induced CNS depression
3) co-administration with other drugs that cause QTc-interval prolongation or drugs that inhibit thioridazine
metabolism or clearance
4) history of cardiac arrhythmias or QTc-interval prolongation
5) hypersensitivity to thioridazine
6) patients with a QTc-interval greater than 450 milliseconds
7) patients with reduced hepatic cytochrome P450 2D6 enzyme activity
8) patients with severe hypertensive or hypotensive heart disease
4) Serious Adverse Effects
a) Thioridazine Hydrochloride
1) Agranulocytosis
2) Cholestatic jaundice syndrome
3) Death
4) Disorder of hematopoietic structure
5) Drug-induced lupus erythematosus, Systemic
6) Ineffective thermoregulation, Heatstroke or hypothermia
7) Leukopenia
8) Neuroleptic malignant syndrome
9) Obstipation
10) Paralytic ileus
11) Priapism
12) Prolonged QT interval
13) Seizure
14) Sudden cardiac death
15) Thrombocytopenia
16) Torsades de pointes
5) Clinical Applications
a) Thioridazine Hydrochloride
1) FDA Approved Indications
a) Schizophrenia, Refractory
1.0 Dosing Information
Drug Properties
Storage and Stability
Exhibit E.18, page 1
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 2 of 84
Page 162 of 244
Adult Dosage
Pediatric Dosage
1.1 Drug Properties
A) Information on specific products and dosage forms can be obtained by referring to the Tradename List (Product
Index)
B) Synonyms
Thioridazine
Thioridazine HCl
Thioridazine Hydrochloride
1.2 Storage and Stability
A) Thioridazine Hydrochloride
1) Oral route
a) Thioridazine tablets should be stored at 25 degrees Celsius (77 degrees Fahrenheit); excursions
permitted to 15 to 30 degrees Celsius (59 to 86 degrees Fahrenheit) (Prod Info Mellaril(R), 2000ae).
b) Thioridazine oral solution should be stored below 30 degrees Celsius (86 degrees Fahrenheit) in a tightly
sealed, amber bottle. The solution can be diluted in distilled water, tap water, or juices; storage of bulk
dilutions is not recommended (Prod Info Mellaril(R), 2000ae).
c) Thioridazine when mixed with lithium citrate syrup (5 and 10 mL) is visually incompatible. Centrifugation
of this mixture yielded two liquid phases, a clear supernatant and a viscous hydrophobic sediment. This
mixture should be avoided due to the possibility that underdosing could occur (Theesen et al, 1981).
1.3 Adult Dosage
Normal Dosage
Dosage in Geriatric Patients
1.3.1 Normal Dosage
1.3.1.A Thioridazine Hydrochloride
1.3.1.A.1 Oral route
1.3.1.A.1.a Schizophrenia, Refractory
1) The usual oral starting dose of thioridazine for schizophrenia unresponsive to other agents is 50
to 100 milligrams three times daily with gradual incremental increases to a maximum of 800
milligrams/day if necessary. The dose should be reduced gradually to determine the minimum
maintenance dose once effective control of symptoms has been achieved (Prod Info Mellaril(R),
2000ae).
1.3.1.A.2 IMPORTANT NOTE
a) Patients being considered for thioridazine therapy should have baseline electrocardiograms and
measurement of serum potassium concentrations. Thioridazine is contraindicated in patients with a
QTc-interval greater than 450 milliseconds and in patients with a history of cardiac arrhythmias. The
drug should not be given until serum potassium levels are within the normal range (Prod Info Mellaril(R),
2000ae).
1.3.1.A.3 MAXIMUM DOSE
a) Thioridazine doses should not exceed 800 milligrams/day as higher doses have been associated
with pigmentation retinopathy and irreversible blindness (Prod Info Mellaril(R), 2000ae).
1.3.1.A.4 ORAL SOLUTION PREPARATION
a) The oral concentrate of thioridazine may be diluted with distilled water, acidified tap water, or
suitable juices. Each dose should be diluted just prior to administration. The preparation and storage of
bulk dilutions is not recommended (Prod Info Mellaril(R), 2000ae).
1.3.4 Dosage in Geriatric Patients
A) Thioridazine Hydrochloride
1) Elderly patients should be treated with reduced doses of phenothiazine drugs and monitored closely for
excessive parkinsonism side effects. This patient population has a higher incidence of these side effects
which may be irreversible and unresponsive to conventional anti-parkinsonian drugs (Ayd, 1961; Paulson,
1968). Unless there are compelling reasons to the contrary, thioridazine use in the elderly should be avoided
because of side effect-related complications.
Exhibit E.18, page 2
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 3 of 84
Page 163 of 244
2) Significantly higher plasma concentrations of thioridazine (1.5- to 2-fold higher) were reported in elderly
patients (mean age, 76 years) as compared with young adults (mean age, 28 years). Adverse effects
(postural hypotension, dry mouth) were more frequent and severe in the elderly subjects. These data
suggest that dosing reductions are indicated in elderly patients receiving thioridazine (Cohen & Sommer,
1988).
1.4 Pediatric Dosage
1.4.1 Normal Dosage
1.4.1.A Thioridazine Hydrochloride
1.4.1.A.1 Oral route
1.4.1.A.1.a Schizophrenia, Refractory
1) For children who suffer from schizophrenia unresponsive to other agents, the recommended
dose of oral thioridazine is 0.5 milligram/kilogram/day in divided doses. Dosage may be titrated
gradually to optimum clinical response or to the maximum dose of 3 milligrams/kilogram/day (Prod
Info Mellaril(R), 2000ae).
1.4.1.A.2 IMPORTANT NOTE
a) Patients being considered for thioridazine therapy should have baseline electrocardiograms and
measurement of serum potassium concentrations. Thioridazine is contraindicated in patients with a
QTc-interval greater than 450 milliseconds and in patients with a history of cardiac arrhythmias. The
drug should not be given until serum potassium levels are within the normal range (Prod Info Mellaril(R),
2000ae).
1.4.1.A.3 MAXIMUM DOSE
a) Thioridazine doses should not exceed 3 milligrams/kilogram/day as higher doses have been
associated with pigmentation retinopathy and irreversible blindness (Prod Info Mellaril(R), 2000ae).
1.4.1.A.4 ORAL SOLUTION PREPARATION
a) The oral concentrate of thioridazine may be diluted with distilled water, acidified tap water, or
suitable juices. Each dose should be diluted just prior to administration. The preparation and storage of
bulk dilutions is not recommended (Prod Info Mellaril(R), 2000ae).
2.0 Pharmacokinetics
Drug Concentration Levels
ADME
2.2 Drug Concentration Levels
A) Thioridazine Hydrochloride
1) Therapeutic Drug Concentration
a) Schizophrenia, not established (Smith et al, 1985; Sajadi et al, 1984; Shvartsburd et al, 1984a).
2.3 ADME
Distribution
Metabolism
Excretion
Elimination Half-life
2.3.2 Distribution
A) Distribution Sites
1) Thioridazine Hydrochloride
a) OTHER DISTRIBUTION SITES
1) CEREBROSPINAL FLUID (Nyberg et al, 1981).
B) Distribution Kinetics
1) Thioridazine Hydrochloride
a) Volume of Distribution
Exhibit E.18, page 3
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 4 of 84
Page 164 of 244
1) 17.8 L/kg (Axelsson, 1977).
2.3.3 Metabolism
A) Metabolism Sites and Kinetics
1) Thioridazine Hydrochloride
a) LIVER, extensive (Sakalis, 1977; Axelsson & Martensson, 1977).
1) Thioridazine disposition was found to be influenced by debrisoquin hydroxylation phenotype
(von Bahr et al, 1991).
B) Metabolites
1) Thioridazine Hydrochloride
a) MESORIDAZINE, active (Cohen et al, 1979; Aguilar, 1975).
1) MESORIDAZINE is twice as potent as THIORIDAZINE and is commercially available as Serentil
(R) (Cohen et al, 1979; Aguilar, 1975).
b) Sulforidazine, (active) (Chakraborty et al, 1989).
c) 5-sulfoxide (ring), inactive (Sakalis, 1977; Axelsson & Martensson, 1977).
2.3.4 Excretion
A) Kidney
1) Thioridazine Hydrochloride
a) Renal Excretion (%)
1) small amounts (Sakalis, 1977; Axelsson & Martensson, 1977).
2.3.5 Elimination Half-life
A) Parent Compound
1) Thioridazine Hydrochloride
a) ELIMINATION HALF-LIFE
1) 21 to 24 hours (Shvartsburd et al, 1984a; Axelsson, 1977).
3.0 Cautions
Contraindications
Precautions
Adverse Reactions
Teratogenicity/Effects in Pregnancy/Breastfeeding
Drug Interactions
3.0.A Black Box WARNING
1) Thioridazine Hydrochloride
a) Oral (Tablet; Solution)
1) Thioridazine hydrochloride has been shown to prolong the QTc interval in a dose related manner, and
drugs with this potential, including thioridazine hydrochloride, have been associated with torsades de
pointes-type arrhythmias and sudden death. Due to its potential for significant, possibly life-threatening,
proarrhythmic effects, thioridazine hydrochloride should be reserved for use in the treatment of
schizophrenic patients who fail to show an acceptable response to adequate courses of treatment with other
antipsychotic drugs, either because of insufficient effectiveness or the inability to achieve an effective dose
due to intolerable adverse effects from those drugs (Prod Info MELLARIL(R) oral tablet, solution, USP,
MELLARIL-S(R) oral suspension, USP, 2000).
3.1 Contraindications
A) Thioridazine Hydrochloride
1) abnormal serum potassium concentration
2) central nervous system (CNS) depression, coma, or drug-induced CNS depression
3) co-administration with other drugs that cause QTc-interval prolongation or drugs that inhibit thioridazine
metabolism or clearance
4) history of cardiac arrhythmias or QTc-interval prolongation
5) hypersensitivity to thioridazine
6) patients with a QTc-interval greater than 450 milliseconds
7) patients with reduced hepatic cytochrome P450 2D6 enzyme activity
8) patients with severe hypertensive or hypotensive heart disease
3.2 Precautions
Exhibit E.18, page 4
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 5 of 84
Page 165 of 244
A) Thioridazine Hydrochloride
1) elderly patients with dementia-related psychosis (unapproved use); increased risk of death reported with both
conventional and atypical antipsychotics when used to treat behavorial and psychological symptoms associated
with dementia (US Food and Drug Administration, 2008)
2) history of breast cancer (can elevate prolactin levels)
3) history of myasthenia gravis
4) history of neuroleptic malignant syndrome or tardive dyskinesia
5) leukopenia or agranulocytosis
6) patients participating in activities requiring complete mental alertness
7) seizure disorders
3.3 Adverse Reactions
Cardiovascular Effects
Dermatologic Effects
Endocrine/Metabolic Effects
Gastrointestinal Effects
Hematologic Effects
Hepatic Effects
Neurologic Effects
Ophthalmic Effects
Reproductive Effects
Respiratory Effects
Other
3.3.1 Cardiovascular Effects
3.3.1.A Thioridazine Hydrochloride
Cardiac dysrhythmia
EKG finding
Hypotension
Prolonged QT interval
Sudden cardiac death
Torsades de pointes
3.3.1.A.1 Cardiac dysrhythmia
a) Ventricular and supraventricular arrhythmias have been reported following therapeutic use of
thioridazine and acute overdose. Arrhythmias have often been associated with conduction defects
manifested by prolonged QRS interval and slight prolongation of the QT interval in association with
either sinus bradycardia or tachycardia (Fletcher et al, 1969). Although in some cases discontinuation of
the drug results in resolution of the cardiac arrhythmias and the return of a normal EKG within 2 weeks
to 4 months (Fletcher et al, 1969), on occasion ventricular tachycardia may be refractory to conventional
Exhibit E.18, page 5
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 6 of 84
Page 166 of 244
modes of therapy including cardioversion, procainamide, and lidocaine. Electrical pacing with a
transvenous electrical pacemaker has been reported to stabilize refractory arrhythmias (Annane et al,
1996) The increased cardiotoxicity of thioridazine over other neuroleptics was confirmed in a
prospective study of neuroleptic overdosage (poisoning) in adult patients presenting to Newcastle
(Australia) Hospitals between 1987-1993 (Buckley et al, 1996).
b) In a retrospective analysis of 141 adult thioridazine mono-intoxications, sinus tachycardia was a
symptom of toxicity in 21% of the cases. The arrhythmia occurred after ingestion of 1125 mg (median;
range 250 to 8000 mg) (Schuerch et al, 1996).
c) A 68-year-old male suffered central nervous, cardiovascular, and gastrointestinal adverse effects
over 9 days after a severe thioridazine intoxication. During high toxic thioridazine plasma concentrations
(6061 to 6480 nanograms/mL), the patient developed life-threatening ventricular arrhythmias followed
by bradycardia. The electrocardiogram showed delays in all parts of the conduction system. A transitory
atrial pacemaker was inserted to maintain a hemodynamically favorable rhythm (Schmidt & Lang,
1997).
3.3.1.A.2 EKG finding
a) Use of thioridazine was found to carry a significant risk for QT interval prolongation in patients on
psychotropic medications, with an odds ratio of 5.4 linking thioridazine therapy with QT interval
abnormalities (p less than 0.001). This conclusion was based on a study using logistic regression and
backwards stepwise regression to determine risk factors for QT interval lengthening in patients enrolled
in psychiatric treatment programs (n=495). Overall, 64 of 495 patients were taking thioridazine. Of the
64 thioridazine-users, 15 (almost 25%) were found to have abnormally lengthened QT intervals. QT
intervals of 456 msec or greater were defined as abnormal, based on a review of electrocardiograms for
101 healthy volunteers. When dose-levels were looked at, only 4 thioridazine-treated patients were
considered to be in the high-dose range (eg, 600 mg/day or greater); however, two of these 4 patients
had abnormally prolonged QT intervals. It was suggested that thioridazine causes this effect by blocking
the delayed rectifier potassium channel in the myocardium, resulting in abnormal repolarization. The
authors concluded that thioridazine confers an increased risk of drug-induced arrhythmias (Reilly et al,
2000).
b) Some data indicate that ECG changes induced by thioridazine, particularly those involving T-waves,
become more severe with increasing age. Although these changes are in most cases asymptomatic,
elderly patients and particularly those with cardiac disease should be monitored (Thornton & Wendkos,
1971).
c) T-wave changes have been reported to represent a reversible benign repolarization disturbance
rather than any indication of cardiotoxic effects. Administration of isosorbide dinitrate, ergotamine,
potassium salts or isoproterenol have been reported to resolve T-wave abnormalities (Pietro, 1981).
d) EKG and serum thioridazine concentrations were studied in 43 patients with paranoid psychosis.
Significant positive correlations were found between serum drug concentrations and type I changes
(rounded, leveled, or notched T-waves) while Type II changes (diphasic waves) showed no
concentration dependence (Axelsson & Asperstrom, 1982).
3.3.1.A.3 Hypotension
a) Labile hypertension occurred in a 62-year-old patient who was treated with thioridazine 200 mg per
day. Within 3 weeks after stopping the thioridazine, episodes of hypertension (systolic 150 to 180,
diastolic 100 to 120) lasting 4 to 8 hours were noted. After reinstituting thioridazine dosage at 300 mg
per day, blood pressure was lowered to normal with no further hypertensive episodes (Thaker et al,
1985).
3.3.1.A.4 Prolonged QT interval
a) Summary
1) Prolongation of the QT interval, along with ventricular and supraventricular arrhythmias, have
been reported following therapeutic use of thioridazine and acute overdose (Reilly et al, 2000; Prod
Info Mellaril(R), 2000ae; Buckley et al, 1996). Due to the association between thioridazine therapy
and QT interval prolongation, the US Food and Drug Administration requested a labeling change as
of July 2000, such that use of thioridazine should be reserved for schizophrenic patients who have
failed to respond to other antipsychotic agents (Anon, 2000). Occasionally, prolongation of the QT
interval has led to the development of torsade de pointes (Kiriike et al, 1987). Rare cases of
hypotension have also occurred (Prod Info Mellaril(R), 2000ae).
b) Incidence: rare
c) Thioridazine lengthens the QTc-interval in a dose-related manner, and drugs with this potential,
including thioridazine, have been associated with arrhythmias of the torsade de pointes-type and
sudden death. In 9 healthy males, QTc-interval increased by 23 milliseconds following a 50-mg dose of
thioridazine (Prod Info Mellaril(R), 2000ae).
3.3.1.A.5 Sudden cardiac death
a) In a large, retrospective, cohort study that included a primary cohort of 93,300 users of antipsychotic
drugs and 186,600 non-users of antipsychotic drugs, there was an increased risk of sudden cardiac
death in adult participants 30 to 74 years of age (mean age of 45.7 years) who were using thioridazine
Exhibit E.18, page 6
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 7 of 84
Page 167 of 244
compared to those who were not using antipsychotic drugs (incidence-rate ratio, 3.19; 95% confidence
interval (CI), 2.41 to 4.21; p less than 0.001). In participants being treated with typical antidepressants
(haloperidol, thioridazine), the incidence-rate ratio for sudden cardiac death increased from 1.31 (95%
CI, 0.97 to 1.77) for those using low doses to 2.42 (95% CI, 1.91 to 3.06) for those using high doses (p
less than 0.001) (Ray et al, 2009).
3.3.1.A.6 Torsades de pointes
a) Incidence: rare
b) Atypical ventricular tachycardia (torsade de pointes) presumably secondary to thioridazine was
reported in a 53-year-old male and was successfully treated with isoproterenol infusion after
unsuccessful use of other agents (Kemper et al, 1983).
c) A 56-year-old schizophrenic patient receiving thioridazine, trifluoperazine, and benztropine
experienced syncope (Raehl et al, 1985). The patient experienced episodes of ventricular tachycardia
with multifocal PVCs and torsade de pointes.
d) A patient had a preexisting prolonged QT interval that led to the development of potentially fatal
ventricular arrhythmia (torsade de pointes) during low-dose, short-term therapy with thioridazine. The
recurrent ventricular tachyarrhythmia was exacerbated by lidocaine and procainamide therapy but was
effectively controlled by cardiac pacing (Kiriike et al, 1987).
e) Complete heart block and torsade de pointes was associated with thioridazine poisoning (3 grams).
A 72-year-old female was semi comatose and had persistent third degree atrioventricular block,
progressive hypotension and torsade de pointes. These symptoms resolved within 48 hours and no
adverse sequelae persisted (Hulisz et al, 1994).
3.3.2 Dermatologic Effects
3.3.2.A Thioridazine Hydrochloride
Erythema multiforme
Pseudolymphoma
3.3.2.A.1 Erythema multiforme
a) Thioridazine 400 and 800 mg orally daily for 17 days was associated with the occurrence of
erythema multiforme of the oral cavity in a 22-year-old patient with psychosis (Rees, 1985).
Improvement of lesions was observed within 48 hours after the discontinuation of thioridazine and
symptomatic treatment.
3.3.2.A.2 Pseudolymphoma
a) A case of pseudolymphoma, manifested by itchy, slightly infiltrated erythemato-popular lesions in the
face exacerbating after sun exposure, was reported in a patient taking thioridazine for 5 1/2 years
(Kardaun et al, 1988). All lesions disappeared four weeks after the drug was discontinued.
3.3.3 Endocrine/Metabolic Effects
3.3.3.A Thioridazine Hydrochloride
Body temperature above normal
Hirsutism
Hyperprolactinemia
Syndrome of inappropriate antidiuretic hormone secretion
Weight gain
3.3.3.A.1 Body temperature above normal
a) Apparent hyperpyrexia was induced by thioridazine in 43-year-old schizophrenic. The patient was
taking 100 mg three times/day and was exposed to a non-air-conditioned environment during prolonged
hot, humid weather (Jacknowitz, 1979).
b) Treatment with thioridazine resulted in hyperpyrexia and ventricular tachycardia in a young woman
who was later shown to have thyrotoxicosis. Authors concluded that hyperthyroidism may enhance
Exhibit E.18, page 7
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 8 of 84
Page 168 of 244
thioridazine toxicity (Murphy & Fitzgerald, 1984).
c) In a study of hypothermia in the elderly, the effects of chlormethiazole, thioridazine, and
lormetazepam were compared. Three out of 14 patients experienced postural hypotension
(chlormethiazole group) while 11 of 14 developed the same reaction following thioridazine.
Chlormethiazole was equal to placebo in hypothermia, while thioridazine and lormetazepam caused a
fall in temperature. For behavior control in the elderly, and for use as a hypnotic, chlormethiazole seems
to be safer than thioridazine or lormetazepam (McCarthy et al, 1986).
3.3.3.A.2 Hirsutism
a) A case of hirsutism associated with long-term thioridazine use (100 mg three times/day for 10 years)
was reported (Phillips et al, 1979).
3.3.3.A.3 Hyperprolactinemia
a) Increased tumor size of a prolactin-secreting pituitary chromophobe adenoma occurred in a 42-yearold schizophrenic male who was receiving thioridazine. Thioridazine was discontinued and the patient
started on bromocriptine 7.5 mg/day to decrease tumor size and diazepam to control anxiety. Peripheral
vision improved and prolactin levels decreased over the next 6 months (Weingarten & Thompson,
1985).
3.3.3.A.4 Syndrome of inappropriate antidiuretic hormone secretion
a) Summary
1) The syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been infrequently
reported with phenothiazines.
b) SIADH was reported in a 42-year-old male receiving thioridazine 400 milligrams daily. The patient
presented with symptoms of hyponatremia (serum sodium of 113 mEq/L), metabolic alkalosis, and
coma. The sodium level returned to normal following discontinuation of thioridazine and supportive
therapy, which included a normal saline infusion. The patient had similar hyponatremic episodes with
other phenothiazine derivatives (Ananth & Lin, 1987).
c) A 58-year-old woman with chronic depression became acutely agitated and received 500 milligrams
of thioridazine within an hour. It was noted that her water consumption increased during a 9-hour
period. The patient was found unresponsive with intermittent seizure activity. Serum sodium was 114
mEq/L, while plasma and urine osmolality were 235 and 512 mOsm/kg, respectively. Fluid restriction
improved the signs and symptoms of SIADH (Vincent & Emery, 1978).
d) One case of syndrome of inappropriate antidiuretic hormone secretion (SIADH) was reported in a
60-year-old schizophrenic patient who received thioridazine 150 milligrams/day for several months. The
patient was comatose, possessed a serum sodium of 112 mEq/L, urine sodium of 17 mEq/L, and serum
and urine osmolality of 239 and 257 mOsm/kg, respectively. A hemogram, ECG, brain scan, and
roentgenograms of the skull, chest, and spine were normal. Thyroid, adrenal, liver, and kidney function
tests were also within normal limits. An EEG revealed a diffuse slow-wave abnormality. The patient was
treated with fluid restriction, regained consciousness, and was subsequently discharged (Matuk &
Kalyanaraman, 1977).
3.3.3.A.5 Weight gain
a) Thioridazine administration was associated with weight gain in acute paranoid psychotic patients.
Participants were divided into 3 subgroups: male patients (25 to 68 years old); female patients younger
than 50 years old; and female patients older than 50 years old. Doses ranged from 80 to 1000
milligrams/day. Out of 8 male patients, 5 experienced a 1% to 10% increase in weight, while 3
demonstrated a 1 to 5% reduction in weight. All 9 female patients, younger than 50 years old, displayed
a 1% to 20% increase in body weight. Eight of 16 female patients older than 50 years old experienced a
1% to 15% increase in weight, 4 individuals maintained their weight, and 3 subjects demonstrated a 1%
to 5% reduction in weight. No specific doses were mentioned to determine if a dose response
relationship existed (Ohman & Axelsson, 1980).
3.3.4 Gastrointestinal Effects
3.3.4.A Thioridazine Hydrochloride
Constipation
Dysphagia
Parotitis
Vomiting
Exhibit E.18, page 8
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Page 9 of 84
Page 169 of 244
Filed 03/24/2010
Xerostomia
3.3.4.A.1 Constipation
a) Constipation and DIARRHEA have been reported with thioridazine therapy (Prod Info Mellaril(R),
2000ae).
3.3.4.A.2 Dysphagia
See Drug Consult reference: ANTIPSYCHOTIC-INDUCED DYSPHAGIA
3.3.4.A.3 Parotitis
a) A 21-year-old female treated with doses of up to 2 g/day of thioridazine with trifluoperazine
developed an enlargement of the parotid glands. Discontinuation of thioridazine resulted in the glands
returning to normal despite continued trifluoperazine administration. Readministration of thioridazine
resulted in gland enlargement. The author postulated that passive congestion as a result of the
atropine-like effects of the phenothiazine caused SALIVARY GLAND ENLARGEMENT (Worthington,
1965).
3.3.4.A.4 Vomiting
a) Vomiting and symptoms of irritability have been associated with abrupt withdrawal of thioridazine
therapy. A 9-year-old male with minimal brain dysfunction treated with 125 mg/day of thioridazine for 18
months developed symptoms of IRRITABILITY, STOMACH PAINS, NAUSEA and vomiting 1 to 3
weeks following abrupt withdrawal of the drug. In addition, dyskinetic movements including
choreoathetotic movements of the hands and fingers associated with facial grimacing also developed
on the fourteenth day post-withdrawal but decreased in frequency lasting up to 90 days (Yepes &
Winsburg, 1977).
3.3.4.A.5 Xerostomia
a) Dryness of the mouth has been reported with thioridazine therapy (Prod Info Mellaril(R), 2000ae).
3.3.5 Hematologic Effects
3.3.5.A Thioridazine Hydrochloride
3.3.5.A.1 Agranulocytosis
a) Summary
1) Leukopenia and agranulocytosis are the most common hematopoietic adverse drug reactions
reported with thioridazine, and the phenothiazine derivatives are frequently implicated in this
reaction. Estimates of the incidence of phenothiazine-induced agranulocytosis vary from 1 to 300
per 100,000 patients.
b) Incidence: rare
c) A female was treated with thioridazine and developed agranulocytosis and THROMBOCYTOPENIA
and subsequently died due to cerebral hemorrhage (Ekblom & Walinder, 1965).
3.3.6 Hepatic Effects
3.3.6.A Thioridazine Hydrochloride
3.3.6.A.1 Hepatotoxicity
a) Summary
1) Nearly all the phenothiazines have been associated with the picture of cholestatic jaundice or
mixed cholestatic-hepatocellular jaundice. Onset of clinical jaundice usually occurs during the
second to fourth week of therapy, but the reaction is not necessarily related to either dose or
duration of therapy.
b) Possible thioridazine-induced hepatic dysfunction was reported in a 38-year-old female who
received thioridazine 300 milligrams/day. Six days following the initiation of thioridazine the patient
became delusional, edematous, and serum AST (aspartate aminotransferase) was 104 units/L (normal
0 to 41 units/L), while ALT (alanine aminotransferase) was 48 units/L (normal 0 to 45 units/L), and LDH
(lactate dehydrogenase) was 376 units/L (normal 100 to 225 units/L). Thioridazine was discontinued
and the serum levels of AST and ALT normalized within 7 days, however the LDH remained elevated
(305 units/L). It is difficult to assess the relationship of thioridazine to the development of transient
hepatic dysfunction, as amitriptyline was administered concurrently (Pies, 1982).
c) Hepatic dysfunction associated with thioridazine which presented with normal bilirubin and normal
liver enzyme levels was reported in a 34-year-old male schizophrenic (Urberg, 1990).
3.3.9 Neurologic Effects
Exhibit E.18, page 9
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 10 of 84
Page 170 of 244
3.3.9.A Thioridazine Hydrochloride
Central nervous system finding
Confusion
Extrapyramidal sign
Neuroleptic malignant syndrome
Parkinsonism
Seizure
Tardive dyskinesia
3.3.9.A.1 Central nervous system finding
a) Summary
1) Drowsiness is common, especially with large doses, but tends to diminish with continued
therapy (Prod Info Mellaril(R), 2000ae). Extrapyramidal symptoms, tardive dyskinesia, and
confusion occur less frequently; however, these side effects are more serious and may require a
reduction in dosage (Theofilopolous et al, 1984; Jeste et al, 1982; Meyer et al, 1983).
b) In a retrospective analysis of 141 adult thioridazine mono-intoxications, the most frequent symptoms
of toxicity, were DROWSINESS and sinus tachycardia (Schuerch et al, 1996). Drowsiness occurred
after ingestion of 1225 mg (median; range 100 to 5000 mg) and sinus tachycardia occurred after
ingestion of 1125 mg (median; range 250 to 8000 mg). The most frequent symptom of intoxication in 61
pediatric cases was drowsiness, which occurred after a median thioridazine ingestion of 4 mg/kg (range
2.2 to 27 mg/kg).
c) A 10-year-old boy treated concurrently with thioridazine and methylphenidate developed persistent
TICS of the head and shoulders. Clonidine did not reduce the tics, suggesting the site of dysfunction is
not within the noradrenergic system (Casat & Wilson, 1986).
d) Two hyperactive boys, who had developed motor and phonic tics during stimulant treatment, reacted
similarly to low doses of haloperidol and thioridazine. Neuroleptic-induced tics may be a consequence
of presynaptic dopamine blockade (Gualtieri & Patterson, 1986).
3.3.9.A.2 Confusion
a) A case of a 35-year-old female treated with thioridazine 25 mg orally 3 times/day developed a toxic
confusion state. Discontinuation of thioridazine and institution of chlordiazepoxide resulted in clearing of
the symptoms (De Hart, 1969).
b) A 67-year-old male treated with thioridazine for chronic brain syndrome developed, at higher
dosages (25 to 50 mg twice a day), a toxic confusional state characterized as hyperactivity, startle
reaction, coma, and Cheyne-Stokes respiration. Lowering of the dosage of the drug to 25 mg/day
resulted in the patient becoming less comatose and less stuporous (Hader & Schulman, 1965).
c) The influence of thioridazine (1 and 1.5 mg/kg) on human cognitive, psychomotor, and reaction
performance as well as subjective feelings was studied. Equivalent doses ranged from 65 to 80 mg and
97 to 120 mg. Performance was reduced in all areas and the most pronounced effects occurred in the
subjective state of well-being. Reaction performance was impaired only at the higher dose. Effects on
cognitive performance varied and showed least correlation with dose (Meyer et al, 1983).
d) Confusion, memory impairment, and cognitive deficits were reported in a 17-year-old female
schizophrenic patient who was treated with thioridazine 200 mg per day and lithium carbonate 1200
mg/day. Lithium levels were nontoxic (0.8 to 0.9 mEq/L) (Bailine & Doft, 1986).
3.3.9.A.3 Extrapyramidal sign
a) Thioridazine has been shown to cause significant impairment of psychomotor performance as
measured by pencil-and-paper tests, critical flicker fusion frequency, wire-maze tracing and tapping.
Doses of 50 mg were evaluated in healthy volunteers (Theofilopolous et al, 1984).
3.3.9.A.4 Neuroleptic malignant syndrome
a) Incidence: rare
b) A case of neuroleptic malignant syndrome (NMS) was reported in a 70-year-old psychiatric patient
who had taken 100 to 300 mg of thioridazine per day for 18 months (Twemlow & Bair, 1983).
c) A neuroleptic malignant syndrome was described in a 22-year-old woman with psychosis following
an increase of her dose of thioridazine to 75 mg daily (Zammit & Sullivan, 1987). The patient responded
Exhibit E.18, page 10
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 11 of 84
Page 171 of 244
initially to withdrawal of thioridazine, however haloperidol administration for 1 day was followed by
return of symptoms. Withdrawal of haloperidol resulted in stabilization; however, the patient remained
psychotic and was eventually treated successfully with chlorpromazine without adverse sequelae.
These data suggest that thioridazine may also cause the neuroleptic malignant syndrome.
3.3.9.A.5 Parkinsonism
a) Summary
1) Contrary to common belief, the results of a retrospective cohort study suggest that atypical
antipsychotics may not be safer than typical antipsychotics when dose and potency are considered
(Rochon et al, 2005).
b) LITERATURE REPORTS
1) The results of a cohort study indicate that high-dose atypical antipsychotic therapy carries a
similar risk for the development of parkinsonism as does typical antipsychotic therapy. In a
population-based, retrospective cohort study, adults (aged 66 years and older) with evidence of
dementia were followed for up to 1 year for the development of parkinsonism symptoms associated
with typical or atypical antipsychotic use. As compared with older adults receiving atypical
antipsychotic therapy (ie, olanzapine, risperidone, quetiapine), incident parkinsonism was 30%
more likely to occur in those taking typical antipsychotics (ie, chlorpromazine, haloperidol,
perphenazine) (adjusted HR, 1.3; 95% CI, 1.04 to 1.58), and 60% less likely to occur in patient who
did not receive either therapy (HR, 0.4; 95% CI, 0.29 to 0.43). Older adults using higher potency
typical antipsychotics had almost a 50% greater risk of experiencing parkinsonism as compared
with patients prescribed atypical antipsychotics (all were considered lower potency) (HR, 1.44; 95%
CI, 1.13 to 1.84); however, in patients receiving lower potency typical antipsychotics, the risk of
developing parkinsonism was no different from that in adults taking atypical antipsychotics (HR,
0.75; 95% CI. 0.48 to 1.15). In addition, a positive dose-related relationship was observed between
the occurrence of incident parkinsonism and the use of atypical antipsychotics. The risk for
developing parkinsonism was more than twice as great in patients using a high-dose atypical
antipsychotic agent as compared with those prescribed a low-dose atypical antipsychotic agent
(HR, 2.07; 95% CI, 1.42 to 3.02). Furthermore, patients taking a typical antipsychotic were found to
have a similar risk for the development of parkinsonism as patients receiving high-dose atypical
antipsychotic therapy (p=ns). The authors conclude that atypical antipsychotics may not be safer
than typical antipsychotics when dose and potency are considered (Rochon et al, 2005).
3.3.9.A.6 Seizure
See Drug Consult reference: ANTIPSYCHOTICS - EFFECT ON SEIZURE THRESHOLD
3.3.9.A.7 Tardive dyskinesia
a) The risk of developing tardive dyskinesia and the likelihood it will become irreversible are thought to
be associated with the duration of therapy and the cumulative dose; the elderly, especially elderly
women, appear to be more prone to this syndrome (Prod Info Mellaril(R), 2000ae).
b) A 17-year-old female treated with 100 to 800 mg/day of thioridazine over a 2-year period developed
tardive dyskinesia. Discontinuation of thioridazine and initiation of Deanol(R) therapy in doses of up to
1200 mg/day resulted in gradual improvement of the condition. After 3 months of deanol therapy the
drug was discontinued, and the symptoms did not return (Kumar, 1976).
c) There was no correlation between serum concentrations of thioridazine and its major metabolites,
THD-2-sulfoxide, THD-2-sulfone, and THD-5-oxide and presence of symptoms of tardive dyskinesia
(TD) in elderly chronic schizophrenic patients (Widerlov et al, 1982). However, another study reported
higher serum concentration-to-dose ratios in 16 middle aged or elderly female patients. Sulforidazine
was significantly elevated in serum of TD patients compared to control (Jeste et al, 1982).
3.3.10 Ophthalmic Effects
3.3.10.A Thioridazine Hydrochloride
Oculogyric crisis
Retinopathy
3.3.10.A.1 Oculogyric crisis
a) Oculogyric crisis has been reported following the use of thioridazine 10 milligrams (Fitzgerald &
Jankovic, 1989).
3.3.10.A.2 Retinopathy
a) Thioridazine has produced pigmentary retinopathy with visual impairment. This effect appears to be
dose related. Patients develop pigmentary changes within 2 to 8 weeks after initiation of therapy with
Exhibit E.18, page 11
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 12 of 84
Page 172 of 244
acute symptoms including blurred vision, night blindness, and partial color blindness. After thioridazine
is discontinued, pigmentary changes may still progress, however, visual function usually improves.
Thioridazine appears to bind to the melanin granules in the retinal pigment epithelium which alters
retinal enzyme kinetics (Shah et al, 1998). The manufacturer cautions not to exceed a maximum daily
dose of 800 mg/day to avoid this adverse effect (Prod Info Mellaril(R), 2000ae).
b) A 28-year-old woman experienced decreased vision in both eyes for 2 weeks after receiving
thioridazine 800 milligrams 4 times daily for 8 weeks. Her dilated fundus revealed a diffuse pigmentary
retinopathy of the entire post-equatorial fundus. With fluorescein angiography, confluent areas of
punctate hyperfluorescence consistent with diffuse retinal pigment epithelial alterations were seen
(Shah et al, 1998).
c) Yellow vision occurred in a patient after receiving thioridazine 25 mg three times/day for 4 days
(Giannini & Mahar, 1980, 1981).
d) Measurement of the oscillatory potentials of the electroretinogram (ERG) and the O2 wavelet may
be necessary to detect early changes of the retina caused by thioridazine therapy. The investigators
feel a daily dosage of 160 mg over the long term or 400 mg for shorter periods are critical levels of drug
administration (Miyata et al, 1980).
e) Two of 18 mentally retarded institutionalized subjects who had received long-term, high dose
treatment with thioridazine or chlorpromazine developed corneal and ventricular opacities (Gualtieri et
al, 1982).
f) PIGMENTARY RETINOPATHY was reported in a 57-year-old woman receiving low doses of
thioridazine (400 mg daily for approximately 15 years) (Lam & Remick, 1985).
g) Three cases of NUMMULAR RETINOPATHY caused by thioridazine were reported. This retinopathy
is a clinical subset of classic thioridazine pigmentation retinopathy. Nummular areas of retinal pigment
epithelial atrophy separated by relatively intact pigment epithelium are found in the midretinal periphery
with sparing of central vision. This can occur with doses of thioridazine previously considered safe
(Kozy et al, 1984). Severe nummular retinopathy and visual dysfunction were reported in a 52-year-old
male with paranoid schizophrenia taking thioridazine 200 milligrams or less, over the past 13 years
(Tekell et al, 1996).
h) A 51-year-old female patient developed pigmentation retinopathy after taking 400 to 800 mg
thioridazine for 2 months. This is below the 800 mg ceiling dose recommended by the manufacturer and
suggests that clinicians should carefully investigate visual complaints of patients taking thioridazine in
the upper end of the approved dosage range (Hamilton, 1985).
i) Thioridazine toxicity to the eye has been described as "progressive chorioretinopathy", but this
designation can be misleading. During the first year after TDZ exposure, retinal pigmentation evolves
from a granular to a patchy or nummular appearance. However, visual function and the
electroretinogram typically improve during this period. Some cases may show chorioretinal atrophy and
functional loss many years later, but there is little evidence for drug-related progression. Late atrophy
may represent degeneration of cells that were injured subclinically during the time of initial drug
exposure. Although TDZ toxicity produces an evolving pigmentary disturbance, functional changes must
be monitored independently of fundus appearance (Marmor, 1990).
3.3.14 Reproductive Effects
3.3.14.A Thioridazine Hydrochloride
Breast cancer
Sexual dysfunction
3.3.14.A.1 Breast cancer
a) Benign INTRADUCTAL PAPILLOMA occurred in a 71-year-old male following approximately 10
years of treatment of thioridazine for a chronic psychiatric disorder (Sara & Gottfried, 1987).
Examination revealed a subareolar mass distending the left nipple with no discharge; the right breast
was unaffected. Six months later, recurrence of a mass in the same breast was observed without pain
or discharge, presumably during continued thioridazine therapy. No data were presented regarding
effects of withdrawal of Mellaril(R) or substitution therapy with other non-phenothiazine psychotropic
agents, and it is impossible to definitely attribute the papilloma to phenothiazine therapy.
3.3.14.A.2 Sexual dysfunction
a) INHIBITION OF EJACULATION related to thioridazine occurred in a 32-year-old patient 1 week after
starting the drug at a dose of 200 mg/day (Yassa, 1983).
b) Four cases of male patients, age range 20 to 40 years, treated with oral thioridazine 100 mg four
times/day developed histories of prolonged PAINFUL ERECTIONS (PRIAPISM) which persisted for 1 to
2 days. All patients were treated with corporeal aspiration and corpus cavernosum-corpus spongiosum
shunts with good results. The authors postulated the mechanism to be due to peripheral adrenergic
Exhibit E.18, page 12
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 13 of 84
Page 173 of 244
blockade (Dorman & Schmidt, 1976).
c) An 11-year-old boy receiving thioridazine for attention deficit disorder presented to the emergency
room with PRIAPISM 30 hours in duration. A penile block with 1% lidocaine was performed. Using a 27
gauge needle inserted into 1 corporeal body, 0.2 to 0.4 milliliters of phenylephrine 1 milligram/milliliter
was instilled every 15 minutes until detumescence occurred. No adverse effects were observed (Siegel
& Reda, 1997).
See Drug Consult reference: DRUG-INDUCED SEXUAL DYSFUNCTION
3.3.15 Respiratory Effects
3.3.15.A Thioridazine Hydrochloride
3.3.15.A.1 Pulmonary embolism
a) The use of psychotropic medications has been linked to an increased risk of fatal pulmonary
embolism. In a case-control study including 62 cases of fatal pulmonary embolism and 243 matched
controls, researchers found that compared to non-use, the current use of conventional antipsychotic
medications (ie, thioridazine and haloperidol) was associated with an increased risk of fatal pulmonary
embolism (adjusted odds ratio, 13.3; 95% confidence interval (CI), 2.3 to 76.3). In addition, low potency
antipsychotics, such as thioridazine, were associated with the highest risk, with an odds ratio of 20.8
(95% CI, 1.7 to 259). The current use of antidepressants was also associated with an increased risk of
fatal pulmonary embolism (adjusted odds ratio, 4.9; 95% CI, 1.1 to 22.5); however, current or past use
of other psychotropic drugs was not associated with an increased risk (adjusted odds ratio, 1.4; 95% CI,
0.3 to 5.8). (Parkin et al, 2003).
3.3.16 Other
3.3.16.A Thioridazine Hydrochloride
Dead - sudden death
Death
Extrapyramidal disease
Withdrawal sign or symptom
3.3.16.A.1 Dead - sudden death
a) Sudden death has been associated with phenothiazines such as thioridazine (Shader & Greenblatt,
1998). Deaths are most likely of cardiac origin and may be attributable to phenothiazine-induced
ventricular tachyarrhythmias.
b) A 68-year-old man being treated with thioridazine 25 milligrams 3 times daily for behavioral
problems was found dead on the fifth day of treatment (Thomas & Cooper, 1998). His post-mortem
examination revealed no coronary thrombosis, myocardial infarction, or other significant pathology
except for ischemic heart disease. The certificate of death noted the cause of death as cardiac
arrhythmia due to ischemic heart disease.
c) Thioridazine was associated with sudden death syndrome in a 20-year-old female hospitalized for
bizarre behavior of 1 week duration and treated initially with chlorpromazine but with subsequent
development of a skin rash (Goodson & Litkenhous, 1976). Therapy was changed to thioridazine 500
mg/day, and the patient remained hospitalized for 1 month, then was discharged. Approximately 7
months later, the patient was again admitted for bizarre behavior and received four 100-mg doses of
chlorpromazine within 2 days before it was discovered that the patient was allergic to the drug.
Treatment was immediately changed to thioridazine in a dose of 200 mg 4 times a day and following 4
days of treatment with thioridazine, the patient was found dead in bed. Autopsy revealed no cause of
death.
3.3.16.A.2 Death
a) Results of a population-based, retrospective cohort study demonstrated that the use of conventional
antipsychotics was associated with an even greater risk for death than atypical antipsychotics when
administered to elderly patients (aged 66 years and older) with dementia. Atypical versus no
antipsychotic use and conventional versus atypical antipsychotic use pair-wise comparisons were
made. A total of 27,259 matched pairs were identified and the dementia cohort was stratified based on
place of residence (community versus long-term care facilities). In order to adjust for difference in
baseline health status, propensity score matching was used. The primary outcome of the study was allcause mortality. The risk for death was evaluated at 30, 60, 120, and 180 days after the antipsychotic
Exhibit E.18, page 13
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 14 of 84
Page 174 of 244
medications were initially dispensed. There was a statistically significant increase in the risk for death at
30 days associated with new use of atypical antipsychotic medications compared with nonuse in both
the community-dwelling cohort (adjusted hazard ratio (HR), 1.31 (95% confidence interval (CI), 1.02 to
1.70); absolute risk difference, 0.2 percentage point) and long-term care cohort (adjusted HR, 1.55
(95% CI, 1.15 to 2.07); absolute risk difference, 1.2 percentage points). For both cohorts, the risk
associated with atypical antipsychotics appeared to persist to 180 days. The risk for death associated
with conventional antipsychotics was even greater than the risk identified with atypical antipsychotics. At
30 days, the adjusted HR for the community-dwelling cohort was 1.55 (95% CI, 1.19 to 2.02) and 1.26
(95% CI, 1.04 to 1.53) for the long-term care cohort (adjusted risk difference for both was 1.1
percentage points). The risk appeared to persist to 180 days for both groups. Some important
limitations to the study include unknown or unmeasured confounders may influence the results and
cause of death could not be examined (Gill et al, 2007).
b) Results of a population-based, retrospective cohort study demonstrated comparable to possibly
greater risk of death associated with the use of conventional antipsychotic medications in the elderly
(aged 65 years and older) compared with atypical antipsychotic medications. The analysis excluded
patients with cancer and included only new users of antipsychotic medications. The primary study
outcome was 180-day all-cause mortality. A set of potential confounders was measured based on
healthcare utilization data within 6 months before the initiation of antipsychotic medications. Of the
37,241 elderly patients identified, 12,882 and 24,359 received conventional and atypical antipsychotic
medications, respectively. The risk of death in the conventional drug group within the first 180 days was
14.1% compared with 9.6% in the atypical drug group (unadjusted mortality ratio, 1.47; 95% confidence
interval (CI), 1.39 to 1.56). In the multi-variable analysis which controlled for potential confounders, the
adjusted mortality ratio for the risk of death within 180 days for conventional versus atypical drug
therapy was 1.32 (95% CI, 1.23 to 1.42). When the most frequently prescribed conventional
antipsychotic drugs were compared with risperidone, the mortality ratio associated with haloperidol was
2.14 (95% CI, 1.86 to 2.45) and loxapine was 1.29 (95% CI, 1.19 to 1.40), while there was no difference
associated with olanzapine. The increased mortality risk for conventional versus atypical drug therapy
was greatest when doses higher (above median) doses were used (mortality ratio 1.67; 95% CI, 1.5 to
1.86) and also during the first 40 days of therapy (mortality ratio 1.6; 95% CI, 1.42 to 1.8). Confirmatory
analyses consisting of multi-variable Cox regression, propensity score, and instrumental variable
estimation confirmed the results of the study (Schneeweiss et al, 2007).
c) The results of a retrospective cohort study indicate that conventional antipsychotic agents are at
least as likely as atypical antipsychotic agents to increase the risk of death among elderly patients 65
years of age or older. The study included 9142 new users of conventional agents (mean age, 83.2
years) and 13,748 new users of atypical agents (mean age, 83.5 years). A higher adjusted relative risk
of death was associated with the use of conventional antipsychotics as compared with atypical
antipsychotics at all timepoints studied after beginning therapy (within 180 days: relative risk (RR), 1.37;
95% confidence interval (CI), 1.27 to 1.49; less than 40 days: RR, 1.56; 95% CI, 1.37 to 1.78; 40 to 79
days: RR, 1.37; 95% CI, 1.19 to 1.59; 80 to 180 days: RR, 1.27; 95% CI, 1.14 to 1.41). In addition, the
adjusted risks of death observed in patients with dementia (RR, 1.29; 95% CI, 1.15 to 1.45), without
dementia (RR, 1.45; 95% CI, 1.30 to 1.63), in a nursing home (RR, 1.26; 95% CI, 1.08 to 1.47), or not in
a nursing home (RR, 1.42; 95% CI, 1.29 to 1.56) were also higher with the use of conventional
antipsychotic therapy as compared with atypical antipsychotic use. This risk appeared to be doserelated and was greater with the use of higher dose (ie, greater than the median) conventional
antipsychotics (RR, 1.73; 95% CI, 1.57 to 1.9). Additional studies which specifically investigate the
optimum care of elderly patients requiring antipsychotic therapy are needed so that appropriate
guidance regarding therapeutic intervention can be provided (Wang et al, 2005).
3.3.16.A.3 Extrapyramidal disease
See Drug Consult reference: NEUROLEPTIC-INDUCED EXTRAPYRAMIDAL REACTIONS
3.3.16.A.4 Withdrawal sign or symptom
a) Labile hypertension occurred in a 62-year-old patient who was treated with thioridazine 200 mg per
day (Thaker et al, 1985). Within 3 weeks after stopping the thioridazine episodes of hypertension
(systolic pressure 150 to 180 mmHg, diastolic pressure 100 to 120 mmHg) lasting 4 to 8 hours were
noted. After reinstituting thioridazine dosage at 300 mg per day, blood pressure was lowered to normal
with no further hypertensive episodes.
3.4 Teratogenicity/Effects in Pregnancy/Breastfeeding
A) Teratogenicity/Effects in Pregnancy
1) Australian Drug Evaluation Committee's (ADEC) Category: C (Batagol, 1996)
a) Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing
harmful effects on the human fetus or neonate without causing malformations. These effects may be
reversible. Accompanying texts should be consulted for further details.
See Drug Consult reference: PREGNANCY RISK CATEGORIES
2) Crosses Placenta: Yes
3) Clinical Management
a) In general, schizophrenia in pregnant patients represents a difficult clinical problem, for which few optimal
Exhibit E.18, page 14
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 15 of 84
Page 175 of 244
treatment options are available. If the benefits of treatment outweigh possible teratogenic risks (ie, if reality
testing demonstrates a risk to life and limb, if the mother demonstrates gross inability to care for herself,
and/or if supportive intervention including hospitalization is inadequate), antipsychotics should be used at
the lowest effective dose to achieve adequate improvement in symptoms (Cohen et al, 1989; Spielvogel &
Wile, 1986). Cautious use of high potency antipsychotics may yield the best therapeutic benefit with the
least anticholinergic and sedative effects, however, clinical evaluations of comparative efficacy and safety
are unavailable in this setting.
4) Literature Reports
a) In pooled data of 2,948 women exposed to phenothiazines during pregnancy, no increased risk for fetal
malformations was demonstrated (relative risk: 1.03; 95% confidence interval: 0.88-1.22). One study did
show a relationship between phenothiazine use and teratogenicity, but the study had many confounders
(Magee et al, 2002).
b) Although phenothiazines have been implicated in several cases of congenital malformations (Freeman,
1972; Rafla, 1987), establishing a definite cause-effect relationship is extremely difficult; the incidence of
malformations does not appear to be greater than that seen in the general population. Most studies have
found phenothiazines to be safe for both mother and fetus if used in low doses during pregnancy (Ayd,
1976; Kris, 1965; Miklovich & van den Berg, 1976).
c) Extrapyramidal symptoms, including hypertonia, tremor, and abnormal hand posturing, which resolved
between 10 and 22 months of age, were reported in an infant maternally exposed to thioridazine,
trifluoperazine, and chlorpromazine (Hill et al, 1966).
B) Breastfeeding
1) Thomson Lactation Rating: Infant risk cannot be ruled out.
a) Available evidence and/or expert consensus is inconclusive or is inadequate for determining infant risk
when used during breastfeeding. Weigh the potential benefits of drug treatment against potential risks
before prescribing this drug during breastfeeding.
2) Clinical Management
a) No reports describing the use of thioridazine during human lactation are available and the effects on the
nursing infant from exposure to the drug in milk are unknown. It is not known if thioridazine affects the
quantity and composition of breastmilk. Until more data is available, use caution when considering the use of
thioridazine in lactating women.
3) Literature Reports
a) No reports describing the use of thioridazine during human lactation or measuring the amount, if any, of
the drug excreted into milk have been located.
4) Drug Levels in Breastmilk
a) Thioridazine Hydrochloride
1) Active Metabolites
a) mesoridazine (Cohen et al, 1979a)
3.5 Drug Interactions
Drug-Drug Combinations
Drug-Food Combinations
Drug-Lab Modifications
3.5.1 Drug-Drug Combinations
Acecainide
Acetylcholine
Ajmaline
Amantadine
Amiodarone
Amisulpride
Amitriptyline
Exhibit E.18, page 15
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 16 of 84
Page 176 of 244
Amoxapine
Aprindine
Arsenic Trioxide
Astemizole
Azimilide
Belladonna
Belladonna Alkaloids
Benztropine
Bepridil
Betel Nut
Bretylium
Bromocriptine
Bupropion
Cabergoline
Chloral Hydrate
Chloroquine
Chlorpromazine
Cinacalcet
Cisapride
Clarithromycin
Clozapine
Darifenacin
Darunavir
Dehydroepiandrosterone
Desipramine
Dibenzepin
Diethylpropion
Disopyramide
Exhibit E.18, page 16
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 17 of 84
Page 177 of 244
Dofetilide
Dolasetron
Doxepin
Droperidol
Duloxetine
Encainide
Enflurane
Erythromycin
Evening Primrose
Fentanyl
Flecainide
Fluconazole
Fluoxetine
Fluvoxamine
Foscarnet
Fosphenytoin
Gatifloxacin
Gemifloxacin
Grepafloxacin
Halofantrine
Haloperidol
Halothane
Hydroquinidine
Ibutilide
Iloperidone
Imipramine
Iopamidol
Isoflurane
Exhibit E.18, page 17
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 18 of 84
Page 178 of 244
Isradipine
Kava
Ketanserin
Lapatinib
Levodopa
Levofloxacin
Levomethadyl
Levorphanol
Lidoflazine
Lithium
Lithospermum
Lorcainide
Lubeluzole
Lumefantrine
Mefloquine
Meperidine
Methadone
Methadone
Metoprolol
Metrizamide
Morphine
Morphine Sulfate Liposome
Moxifloxacin
Nortriptyline
Octreotide
Ondansetron
Orphenadrine
Oxycodone
Exhibit E.18, page 18
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 19 of 84
Page 179 of 244
Paliperidone
Paroxetine
Pentamidine
Phenobarbital
Phenylalanine
Phenytoin
Pimozide
Pindolol
Pirmenol
Porfimer
Prajmaline
Probucol
Procainamide
Procarbazine
Procaterol
Prochlorperazine
Procyclidine
Propafenone
Propranolol
Protirelin
Protriptyline
Quetiapine
Quinidine
Ranolazine
Rilonacept
Risperidone
Ritonavir
Roxithromycin
Exhibit E.18, page 19
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 20 of 84
Page 180 of 244
Sematilide
Sertindole
Sotalol
Sparfloxacin
Spiramycin
Sulfamethoxazole
Sultopride
Sunitinib
Tapentadol
Tedisamil
Telithromycin
Terfenadine
Tetrabenazine
Tramadol
Trazodone
Trifluoperazine
Trihexyphenidyl
Trimethoprim
Trimipramine
Vasopressin
Vitex
Ziprasidone
Zolmitriptan
Zotepine
Zotepine
3.5.1.A Acecainide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although no drug interaction studies have been performed, the manufacturer of thioridazine
states that the concurrent use of thioridazine with other drugs known to prolong the QTc interval is
contraindicated (Prod Info Thioridazine tablets, 2002). Class III antiarrhythmic agents may prolong the QT
Exhibit E.18, page 20
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 21 of 84
Page 181 of 244
interval in some patients, which may result in ventricular tachycardia, ventricular fibrillation, and torsades de
pointes (Yamreudeewong et al, 2003; Prod Info Betapace(R), 2001; Prod Info Corvert(R), 2000; Corey et al,
1999; Karam et al, 1998).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval such as Class III antiarrhythmic agents is contraindicated.
7) Probable Mechanism: additive effect on QT interval
3.5.1.B Acetylcholine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, thioridazine should not be
coadministered with other drugs which are also known to prolong the QTc interval, including acetylcholine
(Prod Info Mellaril(R), 2000f).
3) Severity: contraindicated
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval is contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.C Ajmaline
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Class Ia antiarrhythmics have been shown to prolong the QTc interval at the recommended
therapeutic dose. Even though no formal drug interaction studies have been done, the coadministration of
thioridazine with other drugs known to prolong the QTc interval, including Class Ia antiarrhythmic agents, is
not recommended (Prod Info Mellaril(R), 2002a; Prod Info Procanbid(R), 2000; Prod Info Quinaglute(R),
1999; Desai et al, 1981).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of a Class IA antiarrhythmic and thioridazine is
contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.D Amantadine
1) Interaction Effect: worsening tremor
2) Summary: Worsening of tremor has occurred in elderly patients with Parkinson's disease when
amantadine was co-administered with thioridazine (Prod Info Symmetrel(R), 2002).
3) Severity: minor
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: If amantadine and thioridazine are co-administered, monitor the patient for signs of
tremor emergence or recurrence.
7) Probable Mechanism: unknown
3.5.1.E Amiodarone
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although no drug interaction studies have been performed, the manufacturer of thioridazine
states that the concurrent use of thioridazine with other drugs known to prolong the QTc interval is
contraindicated (Prod Info Thioridazine tablets, 2002). Class III antiarrhythmic agents may prolong the QT
interval in some patients, which may result in ventricular tachycardia, ventricular fibrillation, and torsades de
pointes (Yamreudeewong et al, 2003; Prod Info Betapace(R), 2001; Prod Info Corvert(R), 2000; Corey et al,
1999; Karam et al, 1998).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval such as Class III antiarrhythmic agents is contraindicated.
7) Probable Mechanism: additive effect on QT interval
3.5.1.F Amisulpride
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
Exhibit E.18, page 21
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 22 of 84
Page 182 of 244
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2001b). Several
antipsychotic agents have demonstrated QT prolongation including amisulpride (Prod Info Solian(R), 1999),
haloperidol (O'Brien et al, 1999), pimozide (Prod Info Orap(R), 2000), quetiapine (Owens, 2001c),
paliperidone (Prod Info INVEGA(TM) extended-release oral tablets, 2006), risperidone (Duenas-Laita et al,
1999), sertindole (Agelink et al, 2001), sultopride (Lande et al, 1992), ziprasidone (Prod Info GEODON(R)
intramuscular injection, oral capsule, 2005), and zotepine (Sweetman, 2004).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of agents that prolong the QT interval, such as
antipsychotics, and thioridazine, is contraindicated.
7) Probable Mechanism: additive QT prolongation
3.5.1.G Amitriptyline
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2001). Tricyclic
antidepressants (TCAs) at therapeutic doses can cause QT prolongation (Marshall & Forker, 1982).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Concurrent administration of a tricyclic antidepressant and thioridazine is
contraindicated.
7) Probable Mechanism: additive effect on QT interval
3.5.1.H Amoxapine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2001). Tricyclic
antidepressants (TCAs) at therapeutic doses can cause QT prolongation (Marshall & Forker, 1982).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Concurrent administration of a tricyclic antidepressant and thioridazine is
contraindicated.
7) Probable Mechanism: additive effect on QT interval
3.5.1.I Aprindine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Class I antiarrhythmic agents may prolong the QT interval in some patients, which may result
in ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Although pharmacokinetic studies
between thioridazine and other drugs which prolong the QT interval have not been performed, an additive
effect cannot be excluded. Therefore, the concurrent administration of thioridazine with a Class I
antiarrhythmic agent is contraindicated (Prod Info Rythmol(R), 2002; Prod Info Mellaril(R), 2002; Prod Info
Tambocor(R), 1998).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval, such as Class I antiarrhythmic agents, is contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.J Arsenic Trioxide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, neither thioridazine nor
arsenic trioxide should be coadministered with other drugs which are also known to prolong the QTc interval
(Prod Info Mellaril(R), 2000l; Prod Info Trisenox(R), 2001a).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval, such as arsenic trioxide, is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
Exhibit E.18, page 22
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 23 of 84
Page 183 of 244
8) Literature Reports
a) QT/QTc prolongation should be expected during treatment with arsenic trioxide and torsade de
pointes as well as complete heart block has been reported. Over 460 ECG tracings from 40 patients
with refractory or relapsed APL treated with arsenic trioxide were evaluated for QTc prolongation.
Sixteen of 40 patients (40%) had at least one ECG tracing with a QTc interval greater than 500 msec.
Prolongation of the QTc was observed between 1 and 5 weeks after arsenic trioxide infusion, and then
returned towards baseline by the end of 8 weeks after arsenic trioxide infusion. In these ECG
evaluations, women did not experience more pronounced QT prolongation than men, and there was no
correlation with age (Prod Info Trisenox(R), 2001).
3.5.1.K Astemizole
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, thioridazine should not be
coadministered with other drugs which are also known to prolong the QTc interval, including astemizole
(Prod Info Mellaril(R), 2002; Prod Info Hismanal(R), 1998).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval, such as astemizole, is contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.L Azimilide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although no drug interaction studies have been performed, the manufacturer of thioridazine
states that the concurrent use of thioridazine with other drugs known to prolong the QTc interval is
contraindicated (Prod Info Thioridazine tablets, 2002). Class III antiarrhythmic agents may prolong the QT
interval in some patients, which may result in ventricular tachycardia, ventricular fibrillation, and torsades de
pointes (Yamreudeewong et al, 2003; Prod Info Betapace(R), 2001; Prod Info Corvert(R), 2000; Corey et al,
1999; Karam et al, 1998).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval such as Class III antiarrhythmic agents is contraindicated.
7) Probable Mechanism: additive effect on QT interval
3.5.1.M Belladonna
1) Interaction Effect: increased manic, agitated reactions, or enhanced anticholinergic effects resulting in
cardiorespiratory failure, especially in cases of belladonna overdose
2) Summary: Belladonna contains L-hyoscyamine, atropine, and scopolamine with a total alkaloid content of
at least 0.3% in the leaves and 0.5% in the roots (Blumenthal et al, 1998). The anticholinergic activity of the
active alkaloids present in belladonna may predispose the patient to excessive anticholinergic activity if
taken with a phenothiazine (Shader & Greenblatt, 1971; Taylor et al, 1970a; Louria, 1969a). Because
belladonna is typically available as a homeopathic preparation, the clinical severity of the interaction with
phenothiazines is unknown. Belladonna alkaloids have been used as "spiking" agents in illicit drugs. In the
amount of belladonna used for this purpose, the interaction is well known and severe (Taylor et al, 1970a).
Phenothiazines should not be used to sedate patients with belladonna toxicity; alternatives include shortacting barbiturates, benzodiazepines, or chloral hydrate (Shader & Greenblatt, 1971; Louria, 1969a).
3) Severity: moderate
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Excessive anticholinergic activity may be manifested by dry mouth, constipation,
urinary retention, tachycardia, decreased sweating, mydriasis, blurred vision, elevated temperature,
muscular weakness, and sedation. If such effects are noted, belladonna should be discontinued
immediately. In severe cases, paralytic ileus, confusion, psychoses, agitation, delusions, delirium, and
paranoia may be encountered as well as tachycardia, dysrhythmia, and hypertension. In severe cases,
immediate medical attention should be obtained. Benzodiazepines, short-acting barbiturates, or chloral
hydrate may be used to sedate patients with anticholinergic toxicity (Shader & Greenblatt, 1971).
7) Probable Mechanism: additive anticholinergic effect
8) Literature Reports
a) Central nervous system depression occurred in patients taking an anticholinergic agent with a
phenothiazine. Belladonna alkaloids have been used for "spiking" of illicit drugs. Treatment of toxicity
from such use with a phenothiazine enhances the anticholinergic effects and may lead to coma and
cardiorespiratory failure (Taylor et al, 1970).
b) Use of chlorpromazine to treat drug overdose with the illicit anticholinergic drug 2,5-dimethoxy-4-
Exhibit E.18, page 23
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 24 of 84
Page 184 of 244
methyl amphetamine (STP) enhances mania and agitation, and may result in respiratory failure of
cardiovascular collapse. Diazepam, chlordiazepoxide, or short-acting barbiturates may be treatment of
choice for anticholinergic toxicity (Louria, 1969).
3.5.1.N Belladonna Alkaloids
1) Interaction Effect: increased manic, agitated reactions, or enhanced anticholinergic effects resulting in
cardiorespiratory failure, especially in cases of belladonna overdose
2) Summary: Belladonna contains L-hyoscyamine, atropine, and scopolamine with a total alkaloid content of
at least 0.3% in the leaves and 0.5% in the roots (Blumenthal et al, 1998). The anticholinergic activity of the
active alkaloids present in belladonna may predispose the patient to excessive anticholinergic activity if
taken with a phenothiazine (Shader & Greenblatt, 1971; Taylor et al, 1970a; Louria, 1969a). Because
belladonna is typically available as a homeopathic preparation, the clinical severity of the interaction with
phenothiazines is unknown. Belladonna alkaloids have been used as "spiking" agents in illicit drugs. In the
amount of belladonna used for this purpose, the interaction is well known and severe (Taylor et al, 1970a).
Phenothiazines should not be used to sedate patients with belladonna toxicity; alternatives include shortacting barbiturates, benzodiazepines, or chloral hydrate (Shader & Greenblatt, 1971; Louria, 1969a).
3) Severity: moderate
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Excessive anticholinergic activity may be manifested by dry mouth, constipation,
urinary retention, tachycardia, decreased sweating, mydriasis, blurred vision, elevated temperature,
muscular weakness, and sedation. If such effects are noted, belladonna should be discontinued
immediately. In severe cases, paralytic ileus, confusion, psychoses, agitation, delusions, delirium, and
paranoia may be encountered as well as tachycardia, dysrhythmia, and hypertension. In severe cases,
immediate medical attention should be obtained. Benzodiazepines, short-acting barbiturates, or chloral
hydrate may be used to sedate patients with anticholinergic toxicity (Shader & Greenblatt, 1971).
7) Probable Mechanism: additive anticholinergic effect
8) Literature Reports
a) Central nervous system depression occurred in patients taking an anticholinergic agent with a
phenothiazine. Belladonna alkaloids have been used for "spiking" of illicit drugs. Treatment of toxicity
from such use with a phenothiazine enhances the anticholinergic effects and may lead to coma and
cardiorespiratory failure (Taylor et al, 1970).
b) Use of chlorpromazine to treat drug overdose with the illicit anticholinergic drug 2,5-dimethoxy-4methyl amphetamine (STP) enhances mania and agitation, and may result in respiratory failure of
cardiovascular collapse. Diazepam, chlordiazepoxide, or short-acting barbiturates may be treatment of
choice for anticholinergic toxicity (Louria, 1969).
3.5.1.O Benztropine
1) Interaction Effect: decreased phenothiazine serum concentrations, decreased phenothiazine
effectiveness, enhanced anticholinergic effects (ileus, hyperpyrexia, sedation, dry mouth)
2) Summary: The concurrent use of anticholinergic agents (benztropine, orphenadrine, procyclidine,
trihexyphenidyl) to control extrapyramidal side effects may reduce oral absorption of phenothiazines,
antagonize the behavioral and antipsychotic effects of the phenothiazine, and enhance anticholinergic side
effects (Rivera-Calimlim et al, 1976e; Mann & Boger, 1978g; Singh & Kay, 1979c; Gershon et al, 1965g;
Buckle & Guillebaud, 1967c).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Anticholinergics (benztropine, orphenadrine, procyclidine, trihexyphenidyl) should
not be used routinely with phenothiazine derivatives as prophylaxis against possible extrapyramidal
symptoms; use should be reserved for situations where EPS occur and lowering of the antipsychotic dosage
is not possible. Anticholinergic use should be reevaluated at least every three months.
7) Probable Mechanism: delayed gastric emptying, increased gut wall metabolism of phenothiazine,
decreased absorption
8) Literature Reports
a) The concomitant administration of trihexyphenidyl and chlorpromazine has been shown to result in a
decrease in chlorpromazine plasma levels (Rivera-Calimlim et al, 1973c; Gershon et al, 1965f). A
crossover controlled study of the chlorpromazine-trihexyphenidyl interaction in psychiatric patients
showed conclusively that trihexyphenidyl lowers plasma levels of chlorpromazine from 13% to 100%
(Rivera-Calimlim et al, 1973c). The mechanism by which trihexyphenidyl lowers plasma levels of
chlorpromazine was shown in rats to be an inhibition of gastric emptying by trihexyphenidyl, probably as
a result of its anticholinergic activity (Rivera-Calimlim, 1976c). Slow gastric emptying will delay the
transport of chlorpromazine to intestinal absorption sites and favor enhanced gastrointestinal
metabolism.
b) Trihexyphenidyl may also directly reverse some of the therapeutic effects of chlorpromazine. A toxic
psychosis has been commonly reported following usual therapeutic doses of anticholinergic drugs,
particularly when these agents are used in conjunction with other drugs with anticholinergic properties.
Symptoms may include visual hallucinations, confusion, disorientation, speech difficulty, emotional
Exhibit E.18, page 24
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 25 of 84
Page 185 of 244
lability and psychotic thinking (Perry et al, 1985c).
c) The chlorpromazine-trihexyphenidyl interaction may also include additive anticholinergic effects
including constipation or paralytic ileus, dry mouth, blurred vision, increased intraocular pressure and
urinary retention (Perry et al, 1985c). Hyperpyrexia has been reported, presumably due to blocking of
exocrine sweat glands in combination with the hypothalamic dysregulation produced by antipsychotics
(Mann & Boger, 1978f).
d) A significant reduction in fluphenazine serum levels occurred following addition of procyclidine in
patients who were previously well stabilized. Following discontinuation of procyclidine, fluphenazine
serum levels returned to baseline (Bamrah et al, 1986c). However, the addition of orphenadrine to
perphenazine therapy resulted in no clinically relevant pharmacokinetic changes in the absorption,
distribution, or elimination of perphenazine (Bolvig Hansen et al, 1979c).
3.5.1.P Bepridil
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, bepridil should not be
coadministered with other drugs which are also known to prolong the QTc interval, including phenothiazines
(Prod Info Compazine(R), 2002; Prod Info Mellaril(R), 2002d; Prod Info Stelazine(R), 2002; Prod Info
Thorazine(R), 2002; Prod Info Serentil(R), 2001; Prod Info Vascor(R), 2000).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of bepridil and agents that prolong the QT interval,
such as phenothiazines, is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.Q Betel Nut
1) Interaction Effect: increased extrapyramidal side effects of phenothiazines
2) Summary: Case reports have described increased extrapyramidal side effects when betel nut was
chewed by patients taking fluphenazine and fluphenthixol for schizophrenia (Deahl, 1989a). The
extrapyramidal effects were not improved with anticholinergic therapy with procyclidine, and resolved with
betel nut discontinuation (Deahl, 1989a). A similar effect may occur if betel nut is chewed with other
phenothiazine therapy. The cholinergic activity of betel nut has been attributed to the arecoline content.
When given with peripheral anticholinergics, arecoline increased the heart rate due to central muscarinic
agonist activity (Nutt et al, 1978a). Case reports suggest the onset of betel nut activity to be within 3 weeks
with resolution within 4 to 7 days after discontinuation (Deahl, 1989a).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: It is unclear to what extent the cholinergic effect of betel nut may increase the
incidence of extrapyramidal side effects of phenothiazines, especially if patients are treated with
anticholinergic agents to control these side effects. Deterioration in symptoms of patients with Parkinson's
disease or other extrapyramidal movement disorders may be expected. Persons who have been chewing
betel nut have a characteristic red stain on the teeth which may help the clinician discover betel nut use.
7) Probable Mechanism: cholinergic effect of betel nut
8) Literature Reports
a) Within 3 weeks of initiating betel nut chewing, a 51-year-old Indian man experienced marked rigidity,
bradykinesia, and jaw tremor. This patient had been stabilized on fluphenazine decanoate depot 50
milligrams (mg) every 3 weeks for schizophrenia and procyclidine 5 mg twice daily for a mild
Parkinsonian tremor for the previous 2 years. Within one week of discontinuation of betel nut chewing,
the patient's condition returned to baseline. This report appears to demonstrate decreased
anticholinergic effects of procyclidine when coadministered with betel nut (Deahl, 1989).
b) A 45-year-old Indian man developed akathisia, tremor and stiffness following betel nut ingestion
which was not affected by dosage escalations of up to 20 mg daily of procyclidine. This patient had
been previously stabilized on fluphenthixol 60 mg depot every two weeks for the previous year for
schizoaffective disorder without extrapyramidal side effects. His symptoms resolved over 4 days after
discontinuing betel nut. It appears that the anticholinergic effects of procyclidine were diminished when
betel nut was chewed concomitantly (Deahl, 1989).
c) High doses (5 mg, 10 mg, and 20 mg) of subcutaneous (SC) arecoline given one hour after SC
administration of 0.5 mg of the peripheral anticholinergic agent methscopolamine increased the heart
rate and blood pressure of six Huntington disease patients. Significant increases in blood pressure
occurred at doses of 5 mg, 10 mg (p less than 0.01) and 20 mg (p less than 0.05). Heart rate increased
at doses of 5 mg and 20 mg (p less than 0.01), and 10 mg (p less than 0.05). Subjective effects in some
patients included tremor, flushing or pallor at the time of peak drug effect and nausea, weakness, and
mental changes at the higher doses. No peripheral cholinergic effects were noted. The results indicated
a central muscarinic effect for arecoline (Nutt et al, 1978).
d) A low dose (0.5 mg) of arecoline given intravenously 3 minutes after the peripheral anticholinergic
agent glycopyrrolate 0.15 mg to 8 patients with major depressive disorder increased their heart rates.
Exhibit E.18, page 25
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 26 of 84
Page 186 of 244
The peak heart rate increase in a non-REM portion of the sleep cycle during the 10 minute post-infusion
period was 6.75 +/- 12.9 beats per minute for placebo and 25 +/- 10.3 beats per minute for arecoline.
The peak heart rates all began 1 to 8 minutes after the arecoline infusion, and the mean heart rate was
significantly elevated over placebo from 2 to 10 minutes after arecoline infusion (p less than 0.05)
(Abramson et al, 1985).
e) Though chewing betel nut alone does not significantly increase catecholamine levels, a popular betel
nut preparation does. Six to eight minutes after chewing betel nut, 4 subjects had only a moderate
increase in plasma noradrenaline from 266.2 +/- 105.7 picograms/milliliter (pg/mL) to 313.7 +/- 92.9
pg/mL (p equal to 0.0607). Combining betel nut with lime, catechu and Piper betel flower as is
commonly done caused significant elevation of norepinephrine in nine subjects from 292.2 +/- 59.5
pg/mL to 375.1 +/- 130.0 pg/mL (p equal to 0.0244) and epinephrine from 62.5 +/- 23.9 pg/mL to 102.2
+/- 45.0 pg/mL (p equal to 0.0226). In this group dopamine was also elevated in 8 of 9 subjects, but the
mean was not significant (Chu, 1995).
3.5.1.R Bretylium
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although no drug interaction studies have been performed, the manufacturer of thioridazine
states that the concurrent use of thioridazine with other drugs known to prolong the QTc interval is
contraindicated (Prod Info Thioridazine tablets, 2002). Class III antiarrhythmic agents may prolong the QT
interval in some patients, which may result in ventricular tachycardia, ventricular fibrillation, and torsades de
pointes (Yamreudeewong et al, 2003; Prod Info Betapace(R), 2001; Prod Info Corvert(R), 2000; Corey et al,
1999; Karam et al, 1998).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval such as Class III antiarrhythmic agents is contraindicated.
7) Probable Mechanism: additive effect on QT interval
3.5.1.S Bromocriptine
1) Interaction Effect: decreased bromocriptine effectiveness
2) Summary: Concomitant therapy with thioridazine and bromocriptine was reported to result in interference
of the prolactin lowering effects of bromocriptine. In addition, a deterioration in visual fields was observed
after 3 months of concurrent use, which resolved within 5 days of discontinuing thioridazine (Robbins et al,
1984).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Because bromocriptine and thioridazine have opposite effects on dopamine
receptors, the concurrent use of these two drugs is illogical. Alternative therapy to either drug should be
considered.
7) Probable Mechanism: antagonism at dopamine receptors
3.5.1.T Bupropion
1) Interaction Effect: increased plasma levels of thioridazine
2) Summary: It is recommended that thioridazine, an antipsychotic metabolized by the cytochrome P450
2D6 isoenzyme, be initiated at the lower end of the dose range when administered concomitantly with
bupropion (Prod Info Wellbutrin XL(TM), 2003; Prod Info Zyban(R), 2000).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Coadministration of bupropion and thioridazine should be approached with caution
and should be initiated at the lower end of the dose range of thioridazine. If bupropion is added to the
treatment regimen of a patient already receiving thioridazine, consider decreasing the dose of thioridazine.
7) Probable Mechanism: inhibition of cytochrome P450 2D6-mediated thioridazine metabolism
3.5.1.U Cabergoline
1) Interaction Effect: the decreased therapeutic effect of both drugs
2) Summary: Cabergoline is a long-acting dopamine receptor agonist with a high affinity for dopamine-2
receptors. It should not be administered concomitantly with dopamine-2 antagonists, such as
phenothiazines, butyrophenones, thioxanthines, and metoclopramide (Prod Info Dostinex(R), 1996).
3) Severity: moderate
4) Onset: rapid
5) Substantiation: theoretical
6) Clinical Management: Cabergoline, a dopamine-2 receptor agonist, should not be used concurrently with
a dopamine-2 antagonist, such as thioridazine.
7) Probable Mechanism: antagonistic pharmacologic effects
Exhibit E.18, page 26
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 27 of 84
Page 187 of 244
3.5.1.V Chloral Hydrate
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, thioridazine should not be
coadministered with other drugs which are also known to prolong the QTc interval, including chloral hydrate
(Prod Info Mellaril(R), 2000s; Young et al, 1986).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of chloral hydrate and thioridazine is
contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.W Chloroquine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, thioridazine should not be
coadministered with other drugs which are also known to prolong the QTc interval, including chloroquine
(Prod Info Mellaril(R), 2000ad; Prod Info Aralen(R), 1999).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of chloroquine and agents that prolong the QT
interval, such as thioridazine, is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.X Chlorpromazine
1) Interaction Effect: an increased risk of cardiotoxicity (QT interval prolongation, torsades de pointes,
cardiac arrest)
2) Summary: Because thioridazine may prolong the QT interval and increase the risk of arrhythmias, the
concurrent administration of thioridazine and other phenothiazines is contraindicated (Prod Info Mellaril(R),
2000l). Q and T wave distortions have been observed in patients taking phenothiazines (Prod Info
Compazine(R), 2002a; Prod Info Stelazine(R), 2002a; Prod Info Thorazine(R), 2002a). Other phenothiazines
may have similar effects, though no reports are available.
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of agents that prolong the QT interval, such as
thioridazine and other phenothiazines, is contraindicated.
7) Probable Mechanism: additive effect on QT interval
3.5.1.Y Cinacalcet
1) Interaction Effect: increased thioridazine plasma concentrations
2) Summary: Cinacalcet is partially metabolized by and is a strong inhibitor of the CYP2D6 isozyme.
Cinacalcet may increase blood concentrations of drugs that are predominantly metabolized by CYP2D6 and
have a narrow therapeutic index, such as thioridazine. Therefore, if cinacalcet and thioridazine are
coadministered, dose adjustments of thioridazine may be required (Prod Info SENSIPAR(TM) oral tablets,
2007).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: If cinacalcet, a strong CYP2D6 inhibitor, is coadministered with a drug that is
primarily metabolized by CYP2D6 and has a narrow therapeutic index, such as thioridazine, dose
adjustments of the CYP2D6-metabolized drug may be necessary (Prod Info SENSIPAR(TM) oral tablets,
2007).
7) Probable Mechanism: inhibition of CYP2D6-mediated thioridazine metabolism
3.5.1.Z Cisapride
1) Interaction Effect: cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Cisapride therapy has resulted in serious cardiac arrhythmias, including ventricular
tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation. Because phenothiazines also
may prolong the QT interval and increase the risk of arrhythmias, the concurrent administration of cisapride
with a drug from this class is contraindicated (Prod Info Propulsid(R), 2000).
3) Severity: contraindicated
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: The concurrent use of cisapride and phenothiazines is contraindicated.
Exhibit E.18, page 27
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 28 of 84
Page 188 of 244
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.AA Clarithromycin
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Clarithromycin can prolong the QT interval in some patients, which may result in ventricular
tachycardia, ventricular fibrillation, and torsades de pointes (Prod Info Biaxin(R), 2000). Because
thioridazine may also prolong the QT interval and increase the risk of arrhythmias, the concurrent
administration of clarithromycin and thioridazine is contraindicated (Prod Info Mellaril(R), 2000ac).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of agents that prolong the QT interval, such as
clarithromycin and thioridazine, is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.AB Clozapine
1) Interaction Effect: increased plasma concentrations of clozapine and or the phenothiazine
2) Summary: Coadministration of clozapine with other drugs that are metabolized by cytochrome P450 2D6,
such as phenothiazines, should be approached with caution (Prod Info Clozaril(R), 2002).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: Concomitant use of clozapine with other drugs metabolized by cytochrome P450
2D6, such as phenothiazines, may require lower doses than usually prescribed for either clozapine or the
phenothiazine.
7) Probable Mechanism: competitive substrate inhibition
3.5.1.AC Darifenacin
1) Interaction Effect: increased thioridazine exposure with an increased risk of QT prolongation and other
side effects
2) Summary: Coadministered darifenacin may increase thioridazine exposure, causing a potential risk of QT
prolongation or other serious adverse effects. Thioridazine, like imipramine, is metabolized primarily by the
CYP2D6 isoenzyme and it has a narrow therapeutic window. The mean maximum concentration (Cmax)
and area under the concentration-time curve (AUC) of imipramine increased 57% and 70%, respectively,
when used together with darifenacin 30 mg once daily at steady-state. Note: The recommended dose of
darifenacin is 7.5 or 15 mg once daily. The AUC of desipramine, the active metabolite of imipramine,
increased 3.6-fold. Caution should be used with the coadministration of darifenacin and CYP2D6 substrates
with a narrow therapeutic window, such as thioridazine (Prod Info Enablex, 2004).
3) Severity: major
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Use caution with the coadministration of darifenacin and other CYP2D6 substrates
with a narrow therapeutic window, such as thioridazine. Monitor for thioridazine toxicity including QT
prolongation.
7) Probable Mechanism: competitive inhibition of CYP2D6-mediated thioridazine metabolism
3.5.1.AD Darunavir
1) Interaction Effect: increased thioridazine plasma concentrations
2) Summary: Coadministration of ritonavir-boosted darunavir, a CYP2D6 inhibitor, and thioridazine, a
CYP2D6 substrate, may result in increased plasma concentrations of thioridazine, possibly due to inhibition
of CYP2D6-mediated thioridazine metabolism by darunavir/ritonavir. As this may result in thioridazine
adverse effects, a lower dose of thioridazine should be considered with concomitant use is necessary (Prod
Info PREZISTA(R) film coated oral tablets, 2008).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Concurrent administration of ritonavir-boosted darunavir and thioridazine may
increase thioridazine plasma concentrations. Consider using a lower thioridazine dose when these agents
are coadministered (Prod Info PREZISTA(R) film coated oral tablets, 2008).
7) Probable Mechanism: inhibition of CYP2D6-mediated thioridazine metabolism by darunavir/ritonavir
3.5.1.AE Dehydroepiandrosterone
1) Interaction Effect: reduced effectiveness of phenothiazines
2) Summary: Dehydroepiandrosterone (DHEA) levels within the normal range of 100 to 400
microgram/deciliter (mcg/dL) are conducive to optimal treatment of patients with psychosis (Howard, 1992a).
In case reports, patients have been resistant to antipsychotics when DHEA levels were elevated (Howard,
1992a). Patients being treated with phenothiazines for psychosis should avoid DHEA supplementation.
Exhibit E.18, page 28
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 29 of 84
Page 189 of 244
3) Severity: moderate
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Avoid concomitant use of dehydroepiandrosterone (DHEA) and phenothiazines. If
DHEA is elevated, treatment with dexamethasone 1 mg orally per day may be used to normalize DHEA
levels.
7) Probable Mechanism: elevated dehydroepiandrosterone (DHEA) blood levels may reduce
responsiveness to phenothiazines
8) Literature Reports
a) A 24-year-old female diagnosed with schizophrenia was resistant to daily doses of haloperidol 20
milligrams (mg), fluphenazine 40 mg, lithium carbonate 1200 mg, and lithium carbonate 900 mg plus
thioridazine 300 mg. The patient appeared Cushinoid with moon face, acne, facial hair, abdominal hair,
and a 40 pound weight gain in the previous 8 months. Dehydroepiandrosterone (DHEA) measured as
part of an endocrine panel was 725 micrograms/deciliter (mcg/dL) (normal: 100 to 400 mcg/dL).
Dexamethasone 1 mg orally at bedtime resulted in substantial improvement within one week. The
patient appeared calmer, more alert with improved psychotic symptoms and ability to concentrate. At
two weeks, a repeated DHEA level was within normal range (328 mcg/dL). The author concluded that
elevated DHEA levels were associated with severe psychosis resistant to conventional antipsychotic
therapy (Howard, 1992).
b) A 13-year-old male decompensated with a subsequent two-year period of emotional problems
accompanied by heavy use of LSD, hashish, barbiturates, and alcohol. His mental status included
bizarre, disorganized, delusional thinking, auditory and visual hallucinations, paranoia, lack of attention
to personal hygiene, agitation, and combativeness. He was diagnosed with chronic paranoid
schizophrenia; schizophrenia, chronic undifferentiated type, and schizoaffective disorder, excited type.
He was resistant to daily doses of trifluoperazine 40 mg, chlorpromazine 400 mg, and imipramine 100
mg. He was also resistant to combination therapy with chlorpromazine 400 mg with thiothixene 80 mg,
thioridazine 1000 mg, perphenazine 48 mg with lithium carbonate 1200 mg, clonazepam 4 mg, and
carbamazepine 1200 mg daily. Baseline DHEA level exceeded 900 mcg/dL. A seven-day suppression
test with dexamethasone 1 mg orally at bedtime resulted in a normal DHEA level of 200 mcg/dL. By day
5, psychosis improved and the patient was well-oriented, conversational, and was making good eye
contact. Once dexamethasone was discontinued, rapid decompensation and florid psychosis ensued
despite "substantial amounts of psychotropic medications." DHEA increased to 536 mcg/dL. The author
concluded that elevated DHEA levels were associated with florid psychosis resistant to conventional
antipsychotic therapy (Howard, 1992).
3.5.1.AF Desipramine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2001). Tricyclic
antidepressants (TCAs) at therapeutic doses can cause QT prolongation (Marshall & Forker, 1982).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Concurrent administration of a tricyclic antidepressant and thioridazine is
contraindicated.
7) Probable Mechanism: additive effect on QT interval
3.5.1.AG Dibenzepin
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2001). Tricyclic
antidepressants (TCAs) at therapeutic doses can cause QT prolongation (Marshall & Forker, 1982).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Concurrent administration of a tricyclic antidepressant and thioridazine is
contraindicated.
7) Probable Mechanism: additive effect on QT interval
3.5.1.AH Diethylpropion
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, thioridazine should not be
coadministered with other drugs which are also known to prolong the QTc interval, including diethylpropion
(Prod Info Mellaril(R), 2000z).
3) Severity: contraindicated
Exhibit E.18, page 29
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 30 of 84
Page 190 of 244
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval is contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.AI Disopyramide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Class Ia antiarrhythmics have been shown to prolong the QTc interval at the recommended
therapeutic dose. Even though no formal drug interaction studies have been done, the coadministration of
thioridazine with other drugs known to prolong the QTc interval, including Class Ia antiarrhythmic agents, is
not recommended (Prod Info Mellaril(R), 2002a; Prod Info Procanbid(R), 2000; Prod Info Quinaglute(R),
1999; Desai et al, 1981).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of a Class IA antiarrhythmic and thioridazine is
contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.AJ Dofetilide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although no drug interaction studies have been performed, the manufacturer of thioridazine
states that the concurrent use of thioridazine with other drugs known to prolong the QTc interval is
contraindicated (Prod Info Thioridazine tablets, 2002). Class III antiarrhythmic agents may prolong the QT
interval in some patients, which may result in ventricular tachycardia, ventricular fibrillation, and torsades de
pointes (Yamreudeewong et al, 2003; Prod Info Betapace(R), 2001; Prod Info Corvert(R), 2000; Corey et al,
1999; Karam et al, 1998).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval such as Class III antiarrhythmic agents is contraindicated.
7) Probable Mechanism: additive effect on QT interval
3.5.1.AK Dolasetron
1) Interaction Effect: cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Dolasetron can cause QTc interval prolongation. These changes are related in magnitude and
frequency to the blood levels of the active metabolite, hydrodolasetron. Although the changes in QTc interval
are self-limiting with declining blood levels of hydrodolasetron, some patients may experience prolonged
QTc intervals for 24 hours or longer. Because of dolasetron's ability to cause QTc prolongation, its use with
thioridazine is contraindicated (Prod Info Anzemet(R), 1997; Prod Info Mellaril(R), 2002g).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of dolasetron and thioridazine is contraindicated,
since each of these agents can cause prolongation of the QTc interval.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.AL Doxepin
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2001). Tricyclic
antidepressants (TCAs) at therapeutic doses can cause QT prolongation (Marshall & Forker, 1982).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Concurrent administration of a tricyclic antidepressant and thioridazine is
contraindicated.
7) Probable Mechanism: additive effect on QT interval
3.5.1.AM Droperidol
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturers of some phenothiazines state that concomitant use
Exhibit E.18, page 30
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 31 of 84
Page 191 of 244
with other drugs which prolong the QT interval is contraindicated (Prod Info Thioridazine tablets, 2002). QT
prolongation has been observed in patients treated with droperidol (Prod Info Inapsine(R), 2001). Other
phenothiazines may have similar effects, though no reports are available.
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of droperidol and thioridazine is contraindicated as it
may precipitate QT prolongation.
7) Probable Mechanism: additive cardiac effects
3.5.1.AN Duloxetine
1) Interaction Effect: increased thioridazine serum concentrations and risk of cardiac arrhythmia
2) Summary: Given thioridazine's tendency to prolong the QTc-interval in a dose-dependent manner, the
attendant risk for developing serious or fatal ventricular arrhythmias precludes the safe concomitant use of
duloxetine and thioridazine. Duloxetine is a moderately potent inhibitor of CYP2D6 (for which thioridazine is
a substrate) and therefore, the coadministration of duloxetine with thioridazine is likely to produce elevated
thioridazine plasma concentrations with attendant cardiotoxicity (Prod Info Mellaril(R), 2000c; Prod Info
CYMBALTA(R) delayed-release oral capsules, 2008).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Concomitant use of duloxetine and thioridazine is contraindicated (Prod Info
Mellaril(R), 2000c).
7) Probable Mechanism: duloxetine inhibition of CYP2D6-mediated thioridazine metabolism
3.5.1.AO Encainide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Class I antiarrhythmic agents may prolong the QT interval in some patients, which may result
in ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Although pharmacokinetic studies
between thioridazine and other drugs which prolong the QT interval have not been performed, an additive
effect cannot be excluded. Therefore, the concurrent administration of thioridazine with a Class I
antiarrhythmic agent is contraindicated (Prod Info Rythmol(R), 2002; Prod Info Mellaril(R), 2002; Prod Info
Tambocor(R), 1998).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval, such as Class I antiarrhythmic agents, is contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.AP Enflurane
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, thioridazine should not be
coadministered with other drugs which may also prolong the QTc interval, including enflurane (Owens, 2001;
Prod Info Mellaril(R), 2002b).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that may prolong the QT
interval, such as enflurane, is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.AQ Erythromycin
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Erythromycin significantly increased the mean QTc interval versus baseline in a retrospective
study of 49 patients (Oberg & Bauman, 1995). Erythromycin has demonstrated QTc prolongation in
combination with other drugs that prolong the QT interval (Prod Info PCE(R), 1997). Thioridazine has been
shown to prolong the QT interval; the manufacturer states that the concurrent administration of thioridazine
with other drugs known to prolong the QTc interval is contraindicated (Prod Info Mellaril(R), 2002e).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine with other agents that can prolong
the QT interval, such as erythromycin, is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
Exhibit E.18, page 31
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 32 of 84
Page 192 of 244
3.5.1.AR Evening Primrose
1) Interaction Effect: increased risk of seizures
2) Summary: Evening primrose oil may reduce the seizure threshold when taken with phenothiazines.
Seizures have been reported when evening primrose oil was added to phenothiazine therapy in
schizophrenic patients (Holman & Bell, 1983a; Vaddadi, 1981a). Avoid concomitant use of evening primrose
oil with anticonvulsants.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Avoid concomitant use of evening primrose oil with phenothiazines.
7) Probable Mechanism: evening primrose oil may reduce the seizure threshold
8) Literature Reports
a) A 43-year-old male on fluphenazine decanoate 50 mg every two weeks experienced a grand mal
seizure after 12 weeks of using EPO 4 grams daily. After withdrawing EPO, no further seizure episodes
occurred in the next 7 months (Holman & Bell, 1983).
b) Three schizophrenic patients unresponsive to phenothiazines were given evening primrose oil
(EPO), which exacerbated symptoms and led to seizures. EPO was discontinued and carbamazepine
initiated when electroencephalogram (EEG) showed temporal lobe epileptic disorders. Phenothiazine
therapy was discontinued or reduced in all patients (Vaddadi, 1981).
3.5.1.AS Fentanyl
1) Interaction Effect: an increase in central nervous system and respiratory depression
2) Summary: The concomitant use of fentanyl and other central nervous system depressants including
phenothiazines (e.g. chlorpromazine, promethazine, thioridazine) may result in additive CNS and respiratory
depressant effects, including hypotension, profound sedation and/or coma . When administering fentanyl
and a phenothiazine together, one or both agents dosage should be significantly reduced (Prod Info
Duragesic(R), 2005). Monitor patient carefully for signs of respiratory depression, CNS depression, and
hypotension.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Monitor patients for signs of respiratory depression, CNS depression, and
hypotension. A dosage reduction of one or both drugs should be made.
7) Probable Mechanism: additive effects
3.5.1.AT Flecainide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Class I antiarrhythmic agents may prolong the QT interval in some patients, which may result
in ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Although pharmacokinetic studies
between thioridazine and other drugs which prolong the QT interval have not been performed, an additive
effect cannot be excluded. Therefore, the concurrent administration of thioridazine with a Class I
antiarrhythmic agent is contraindicated (Prod Info Rythmol(R), 2002; Prod Info Mellaril(R), 2002; Prod Info
Tambocor(R), 1998).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval, such as Class I antiarrhythmic agents, is contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.AU Fluconazole
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2000i). Other
phenothiazines may have similar effects, though no reports are available. Case reports have described QT
prolongation and torsades de pointes associated with fluconazole (Khazan & Mathis, 2002; Wassmann et al,
1999).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Due to the possibility of additive effects on the QT interval, the concomitant
administration of fluconazole and thioridazine is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.AV Fluoxetine
Exhibit E.18, page 32
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 33 of 84
Page 193 of 244
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Fluoxetine inhibits the metabolism of thioridazine through inhibition of CYP2D6. The resulting
elevated levels of thioridazine may enhance QT prolongation (Prod Info Mellaril(R), 2000w). Fluoxetine has
been shown to prolong the QTc interval at the recommended therapeutic dose (Prod Info Prozac(R), 2001).
Although citing no data, the manufacturer of thioridazine states that concomitant use with other drugs which
prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2000w).
3) Severity: contraindicated
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: The concurrent administration of fluoxetine and thioridazine is contraindicated.
7) Probable Mechanism: inhibition of cytochrome P450 2D6-mediated thioridazine metabolism; additive
effects on QT prolongation
3.5.1.AW Fluvoxamine
1) Interaction Effect: an increased risk of thioridazine toxicity, cardiotoxicity (QT prolongation, torsades de
pointes, cardiac arrest)
2) Summary: Fluvoxamine inhibits the metabolism of thioridazine, possibly through the inhibition of
cytochrome P450 2D6 (CYP2D6) resulting in toxicity. The resulting elevated levels of thioridazine would be
expected to enhance the prolongation of the QT interval associated with thioridazine and may increase the
risk of serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes-type arrhythmias (Prod Info
Mellaril(R), 2000r).
3) Severity: contraindicated
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Due to the potential for significant, possibly life-threatening, proarrhythmic effects,
concurrent administration of thioridazine and fluvoxamine is contraindicated.
7) Probable Mechanism: inhibition of cytochrome P450 2D6-mediated thioridazine metabolism
8) Literature Reports
a) The serum concentrations of thioridazine and its two metabolites, mesoridazine and sulforidazine,
were evaluated in ten male schizophrenic patients aged 36 to 78 years at three separate time points. All
patients were receiving thioridazine monotherapy for the management of schizophrenia at a mean dose
of 88 mg daily. Fluvoxamine 50 mg daily was coadministered for one week. Plasma levels of
thioridazine and its metabolites were measured during monotherapy with thioridazine, after one week of
concurrent therapy with thioridazine and fluvoxamine, and two weeks after fluvoxamine was
discontinued. Following one week of combination therapy with fluvoxamine and thioridazine,
thioridazine levels increased 225%, mesoridazine levels increased 219%, and sulforidazine
concentrations rose 258%. Even two weeks after the discontinuation of fluvoxamine, three patients
continued to show elevated thioridazine and metabolite levels. No clinical symptoms were attributed to
the interaction between these two agents (Carrillo et al, 1999).
b) The metabolism of thioridazine is inhibited by drugs such as fluvoxamine due to reduced cytochrome
P450 2D6 and 1A2 isozyme activity. The elevated levels of thioridazine would be expected to enhance
the prolongation of the QT interval associated with thioridazine. This, in turn, may increase the risk of
serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes-type arrhythmias (Prod Info
Mellaril(R), 2000q).
3.5.1.AX Foscarnet
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Foscarnet can prolong the QT interval in some patients, which may result in ventricular
tachycardia, ventricular fibrillation, and torsades de pointes (Prod Info Foscavir(R), 1998). Because
thioridazine may also prolong the QT interval and increase the risk of arrhythmias, the concurrent
administration of foscarnet and thioridazine is contraindicated (Prod Info Mellaril(R), 2000g).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of foscarnet and thioridazine is contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.AY Fosphenytoin
1) Interaction Effect: increased or decreased phenytoin levels and possibly reduced phenothiazine levels
2) Summary: Fosphenytoin is a prodrug of phenytoin and the same interactions that occur with phenytoin
are expected to occur with fosphenytoin (Prod Info Cerebyx(R), 1999). Concurrent phenothiazine and
phenytoin therapy has been reported to increase, decrease, or cause no change in the serum levels of
phenytoin (Sands et al, 1987; Vincent, 1980; Siris et al, 1974; Houghton & Richens, 1975). In one study,
concomitant phenytoin reduced the serum levels of mesoridazine, but not thioridazine (Linnoila et al, 1980a).
3) Severity: minor
4) Onset: delayed
Exhibit E.18, page 33
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 34 of 84
Page 194 of 244
5) Substantiation: probable
6) Clinical Management: Consider monitoring phenytoin levels when a phenothiazine is added or
discontinued from therapy; dosage adjustments may be needed in some cases. The patient should also be
observed for any signs of phenytoin toxicity (ataxia, nystagmus, tremor, hyperreflexia), particularly in the
case of adjustments to the phenothiazine dosage. Observe patients for phenothiazine efficacy.
7) Probable Mechanism: induction or inhibition of phenytoin metabolism; induction of phenothiazine
metabolism
8) Literature Reports
a) Compelling data were reported suggesting that phenothiazines as a group decrease serum
phenytoin concentrations, but the effect of individual phenothiazines was not evaluated. A total of 92
cases (institutionalized patients) who were receiving constant phenytoin doses and who were either
initiating, discontinuing, increasing, or decreasing a phenothiazine were retrospectively reviewed.
Approximately half of the patients received thioridazine, while the other half received either
chlorpromazine or mesoridazine. Phenytoin concentrations decreased by 44% (p=0.001) when a
phenothiazine was added; similarly, increases in phenothiazine dose caused a 33% decrease in
phenytoin concentrations (p=0.001). In patients who discontinued a phenothiazine, phenytoin
concentrations increased by 71% (p=0.001); similarly, decreases in phenothiazine dose caused a 55%
increase in phenytoin concentrations (p=0.001). Although the combined results cannot be applied
clinically to a particular phenothiazine, this study does suggest a remarkably strong trend among
phenothiazines which is contrary to some individual case reports. Further study is needed
(Haidukewych & Rodin, 1985).
b) The effects of concomitant treatment with phenytoin and/or phenobarbital on the steady-state serum
concentrations of haloperidol, thioridazine, and mesoridazine were investigated in 2 groups of patients.
The investigators found that concomitant anticonvulsant medication significantly reduced the plasma
level of haloperidol and mesoridazine, but not thioridazine (Linnoila et al, 1980).
3.5.1.AZ Gatifloxacin
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Gatifloxacin may prolong the QT interval in some patients, which may result in ventricular
tachycardia, ventricular fibrillation, and torsades de pointes (Prod Info Tequin(TM), 1999). Although
pharmacokinetic studies between gatifloxacin and other drugs which prolong the QT interval have not been
performed, an additive effect cannot be excluded. According to the manufacturer, thioridazine should not be
administered with other drugs which are also known to prolong the QTc interval (Prod Info Mellaril(R),
2000h).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of gatifloxacin and thioridazine is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.BA Gemifloxacin
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although pharmacokinetic studies between thioridazine and gemifloxacin, which may prolong
the QT interval, have not been performed, gemifloxacin should not be used in patients receiving thioridazine
(Prod Info Factive(R), 2003).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: The concurrent administration of thioridazine with other drugs that prolong the QT
interval, such as gemifloxacin, is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.BB Grepafloxacin
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Healthy volunteers who received grepafloxacin during a Phase I study experienced
prolongation of the QTc interval. On an outpatient basis, grepafloxacin is contraindicated with other drugs
that are known to also prolong the QTc interval or cause torsades de pointes, including phenothiazines.
When appropriate cardiac monitoring can be assured, such as in the hospitalized patient, these two agents
should be coadministered with caution (Prod Info Raxar(R), 1999).
3) Severity: contraindicated
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: The concurrent use of grepafloxacin and phenothiazines is contraindicated unless
appropriate cardiac monitoring can be assured, such as in the hospitalized patient.
7) Probable Mechanism: additive cardiac effects
Exhibit E.18, page 34
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 35 of 84
Page 195 of 244
3.5.1.BC Halofantrine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Halofantrine can prolong the QT interval in some patients, which may result in ventricular
tachycardia, ventricular fibrillation, and torsades de pointes (Prod Info Halfan(R), 1998). Because
thioridazine may also prolong the QT interval and increase the risk of arrhythmias, the concurrent
administration of halofantrine with thioridazine is contraindicated (Prod Info Thioridazine tablets, 2002).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Due to the potential for additive effects on the QT interval, the concurrent
administration of halofantrine and thioridazine is contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.BD Haloperidol
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2001b). Several
antipsychotic agents have demonstrated QT prolongation including amisulpride (Prod Info Solian(R), 1999),
haloperidol (O'Brien et al, 1999), pimozide (Prod Info Orap(R), 2000), quetiapine (Owens, 2001c),
paliperidone (Prod Info INVEGA(TM) extended-release oral tablets, 2006), risperidone (Duenas-Laita et al,
1999), sertindole (Agelink et al, 2001), sultopride (Lande et al, 1992), ziprasidone (Prod Info GEODON(R)
intramuscular injection, oral capsule, 2005), and zotepine (Sweetman, 2004).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of agents that prolong the QT interval, such as
antipsychotics, and thioridazine, is contraindicated.
7) Probable Mechanism: additive QT prolongation
3.5.1.BE Halothane
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, thioridazine should not be
coadministered with other drugs which may also prolong the QTc interval, including halothane (Owens,
2001b; Prod Info Mellaril(R), 2002).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that may prolong the QT
interval, such as halothane, is contraindicated.
7) Probable Mechanism: additive effects on the QT interval
3.5.1.BF Hydroquinidine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Class Ia antiarrhythmics have been shown to prolong the QTc interval at the recommended
therapeutic dose. Even though no formal drug interaction studies have been done, the coadministration of
thioridazine with other drugs known to prolong the QTc interval, including Class Ia antiarrhythmic agents, is
not recommended (Prod Info Mellaril(R), 2002a; Prod Info Procanbid(R), 2000; Prod Info Quinaglute(R),
1999; Desai et al, 1981).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of a Class IA antiarrhythmic and thioridazine is
contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.BG Ibutilide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although no drug interaction studies have been performed, the manufacturer of thioridazine
states that the concurrent use of thioridazine with other drugs known to prolong the QTc interval is
contraindicated (Prod Info Thioridazine tablets, 2002). Class III antiarrhythmic agents may prolong the QT
interval in some patients, which may result in ventricular tachycardia, ventricular fibrillation, and torsades de
pointes (Yamreudeewong et al, 2003; Prod Info Betapace(R), 2001; Prod Info Corvert(R), 2000; Corey et al,
Exhibit E.18, page 35
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 36 of 84
Page 196 of 244
1999; Karam et al, 1998).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval such as Class III antiarrhythmic agents is contraindicated.
7) Probable Mechanism: additive effect on QT interval
3.5.1.BH Iloperidone
1) Interaction Effect: an increased risk of QT interval prolongation
2) Summary: Due to the potential for additive effects on the QT interval and increased risk of torsade de
pointes, caution should be used when iloperidone and drugs that prolong the QT interval are given
concomitantly. Consideration should be given to monitoring cardiac function periodically with on-treatment
ECGs and evaluating electrolyte (ie, magnesium, potassium) levels. Discontinue iloperidone in patients with
persistent QTc measurements greater than 500 msec (Prod Info FANAPT(TM) oral tablets, 2009).
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Concomitant use of iloperidone and drugs that prolong the QT interval may result
in additive effects on the QT interval and an increased risk of torsade de pointes. Iloperidone should be
avoided in patients with significant cardiovascular illness, eg, cardiac arrhythmia, QT prolongation, recent
acute myocardial infarction, and uncompensated heart failure. If concomitant use is necessary, consider
monitoring cardiac function periodically with on-treatment ECGs and evaluating electrolyte (ie, magnesium,
potassium) levels. Discontinue iloperidone in patients with persistent QTc measurements greater than 500
msec(Prod Info FANAPT(TM) oral tablets, 2009).
7) Probable Mechanism: additive effects on the QT interval
8) Literature Reports
a) In an open-label QTc study of patients with schizophrenia or schizoaffective disorder (n=160),
iloperidone 12 mg twice a day was associated with QTc prolongation of 9 msec (Prod Info FANAPT(TM)
oral tablets, 2009).
3.5.1.BI Imipramine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2001). Tricyclic
antidepressants (TCAs) at therapeutic doses can cause QT prolongation (Marshall & Forker, 1982).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Concurrent administration of a tricyclic antidepressant and thioridazine is
contraindicated.
7) Probable Mechanism: additive effect on QT interval
3.5.1.BJ Iopamidol
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, thioridazine should not be
coadministered with other drugs which are also known to prolong the QTc interval, including iopamidol (Prod
Info Mellaril(R), 2000d).
3) Severity: contraindicated
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval is contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.BK Isoflurane
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, thioridazine should not be
coadministered with other drugs which may also prolong the QTc interval, including isoflurane (Owens,
2001a; Prod Info Mellaril(R), 2002c).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that may prolong the QT
interval, such as isoflurane, is contraindicated.
Exhibit E.18, page 36
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 37 of 84
Page 197 of 244
7) Probable Mechanism: additive effects on the QT interval
3.5.1.BL Isradipine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Isradipine can prolong the QT interval in some patients, which may result in ventricular
tachycardia, ventricular fibrillation, and torsades de pointes (Prod Info DynaCirc(R), 2000). Because
thioridazine may also prolong the QT interval and increase the risk of arrhythmias, the concurrent
administration of isradipine with thioridazine is contraindicated (Prod Info Mellaril(R), 2000v).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of isradipine and thioridazine is contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.BM Kava
1) Interaction Effect: additive dopamine antagonist side effects
2) Summary: Theoretically, kava may add to the dopamine antagonism of phenothiazines, increasing the
risk for adverse effects. Case reports describe what appears to be dopamine-blocking activity of kava
manifested in patients as dystonia, dyskinesias, and Parkinsonism (Spillane et al, 1997a; Schelosky et al,
1995a). Kava extracts antagonized apomorphine-induced hyperreactivity to external stimuli in mice,
suggesting dopamine blockade activity (Jamieson et al, 1989a).
3) Severity: moderate
4) Onset: rapid
5) Substantiation: theoretical
6) Clinical Management: Avoid concomitant use of kava with phenothiazines. The desired effect and/or
adverse effects of phenothiazines may be increased or may be variable depending on the time of
administration of kava and the quality of the kava product (i.e., whether it consistently contains a
standardized amount of kava).
7) Probable Mechanism: additive dopamine antagonism
8) Literature Reports
a) A 27-year-old Aboriginal Australian male presented three times following heavy kava use with
symptoms of severe choreoathetosis of the limbs, trunk, neck, and facial musculature, and athetosis of
the tongue. Level of consciousness was not impaired. Symptoms resolved within 12 hours of
intravenous diazepam on each occasion. Acute rheumatic fever was excluded, cerebrospinal fluid and
computed tomography of the brain was normal, and urinary drug screen was negative. The only
abnormalities found in hematological and biochemical tests were a serum alkaline phosphatase of 162
international units/liter (IU/L) (normal: 35-135 IU/L) and serum gamma-glutamyltransferase of 426 IU/L
(normal less than 60 IU/L). These were attributed to kava use. The patient did not drink alcohol
(Spillane et al, 1997).
b) A 76-year-old female with idiopathic Parkinson's disease of 17 years' duration treated for 8 years
with levodopa 500 milligrams (mg) and benserazide 125 mg was prescribed kava extract (Kavasporal
Forte(R)) 150 mg twice daily for complaints of inner tension. Within 10 days, she noted a pronounced
increase in her daily "off" periods both in terms of duration and number. Within 2 days of discontinuing
the kava product, symptoms had returned to her normal baseline (Schelosky et al, 1995).
c) A 63-year-old female experienced sudden and acute forceful involuntary oral and lingual dyskinesias
on the fourth day of self-initiated therapy with kava extract (Kavasporal Forte(R)) 150 mg three times
daily. She was treated successfully in the emergency room with biperiden 5 mg intravenously. She
denied taking any other medications in the months preceding this event (Schelosky et al, 1995).
d) A 22-year-old female took kava extract (Laitan(R)) 100 mg once for anxiety and nervousness. Within
four hours she experienced oral and lingual dyskinesias, tonic rotation of the head, and painful twisting
trunk movements. She was treated successfully with biperiden 2.5 mg intravenously. She denied taking
any other medications in the months preceding this event (Schelosky et al, 1995).
e) A 28-year-old male experienced acute involuntary neck extension with forceful upward deviation of
the eyes within 90 minutes of taking kava extract (Laitan(R)) 100 mg. Symptoms resolved
spontaneously within 40 minutes. This man had a history of acute dystonic reactions following exposure
to promethacin (50 mg) and fluspirilene (1.5 mg), which had responded biperiden 5 mg intravenously 9
and 12 years previously (Schelosky et al, 1995).
f) In mice, kava extracts antagonized apomorphine-induced hyperreactivity to external stimuli. The
number of hyperreactive mice after apomorphine 20 milligrams/kilogram (mg/kg) intraperitoneal
administration was 6/6 in the saline treated group versus 0/6 in the group treated with kava resin (120
mg/kg) (p less than 0.005) or aqueous kava extract (p less than 0.001) (Jamieson et al, 1989).
3.5.1.BN Ketanserin
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, thioridazine should not be
coadministered with other drugs which are also known to prolong the QTc interval, including ketanserin
Exhibit E.18, page 37
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 38 of 84
Page 198 of 244
(Prod Info Mellaril(R), 2000a).
3) Severity: contraindicated
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval is contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.BO Lapatinib
1) Interaction Effect: an increased risk of QT interval prolongation
2) Summary: Due to the potential for additive effects on the QT interval and increased risk of torsade de
pointes, caution should be used when lapatinib and drugs that prolong the QT interval are given
concomitantly. Consideration should be given to monitoring cardiac function periodically with on-treatment
ECGs and evaluating electrolyte (ie, magnesium, potassium) levels (Prod Info TYKERB oral tablets, 2008).
Thirteen patients had either QTcF (corrected QT by the Friedericia method) greater than 480 msec or an
increase in QTcF of greater than 60 msec in an uncontrolled, open-label, dose escalation study in advanced
cancer patients (n=81) who received lapatinib doses ranging from 175 mg/day to 1800 mg/day, with serial
ECGs collected on days 1 and 14 (Prod Info TYKERB oral tablets, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Concomitant use of lapatinib and drugs that prolong the QT interval may result in
additive effects on the QT interval and an increased risk of torsade de pointes. Therefore, caution should be
used when these agents are given concomitantly. Consider monitoring cardiac function periodically with ontreatment ECGs and evaluating electrolyte (ie, magnesium, potassium) levels (Prod Info TYKERB oral
tablets, 2008).
7) Probable Mechanism: additive effects on the QT interval
3.5.1.BP Levodopa
1) Interaction Effect: loss of levodopa efficacy
2) Summary: Because thioridazine is a dopamine antagonist, it is expected to antagonize the
pharmacologic effects of levodopa (Prod Info Stalevo(TM), 2003; Prod Info Sinemet(R), 1998). In general,
concomitant use should be avoided (Yahr & Duvoisin, 1972).
3) Severity: moderate
4) Onset: rapid
5) Substantiation: theoretical
6) Clinical Management: Concurrent use of thioridazine and levodopa should be avoided. If concomitant
use is necessary, monitor the patient for loss of levodopa therapeutic efficacy.
7) Probable Mechanism: pharmacologic antagonism
3.5.1.BQ Levofloxacin
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Coadministration of levofloxacin and thioridazine may produce additive prolongation of the
QTc interval and, thus, such use is contraindicated (Prod Info Mellaril(R), 2002; Prod Info Levaquin(R),
2000).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval, such as levofloxacin, is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.BR Levomethadyl
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, thioridazine should not be
coadministered with other drugs which are also known to prolong the QTc interval, including levomethadyl
(Prod Info Mellaril(R), 2002; Prod Info Orlaam(R), 2001).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Levomethadyl is contraindicated in patients being treated with thioridazine as it
may precipitate QT prolongation.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.BS Levorphanol
1) Interaction Effect: an increase in central nervous system and respiratory depression
Exhibit E.18, page 38
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 39 of 84
Page 199 of 244
2) Summary: The concomitant use of levorphanol and other central nervous system depressants including
phenothiazines (e.g. chlorpromazine, promethazine, thioridazine) may result in additive CNS and respiratory
depressant effects, including hypotension, profound sedation and/or coma . When administering levorphanol
and a phenothiazine together, one or both agents dosage should be significantly reduced (Prod Info LEVODROMORAN(TM) injection, oral tablets, 2004). Monitor patient carefully for signs of respiratory depression,
CNS depression, and hypotension.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Monitor patients for signs of respiratory depression, CNS depression, and
hypotension. A dosage reduction of one or both drugs should be made.
7) Probable Mechanism: additive effects
3.5.1.BT Lidoflazine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, thioridazine should not be
coadministered with other drugs which are also known to prolong the QTc interval, including lidoflazine
(Prod Info Mellaril(R), 2000b; Hanley & Hampton, 1983).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of lidoflazine and thioridazine is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.BU Lithium
1) Interaction Effect: weakness, dyskinesias, increased extrapyramidal symptoms, encephalopathy, and
brain damage
2) Summary: An encephalopathic syndrome followed by irreversible brain damage has occurred in a few
patients treated with lithium plus a dopamine-2 antagonist, particularly haloperidol. A causal relationship
between these events and the concomitant administration of a dopamine-2 antagonist and lithium has not
been established (Prod Info LITHOBID(R) slow-release oral tablets, 2005). Coadministration of lithium and a
number of antipsychotic drugs has caused a wide variety of encephalopathic symptoms, brain damage,
extrapyramidal symptoms, and dyskinesias in isolated case reports. In most cases, these effects have
occurred with therapeutic lithium levels (Amdisen, 1982; Prakash, 1982; Addonizio et al, 1988a). However,
many series and trials have reported using such combinations with no severe adverse consequences
(Goldney & Spence, 1986). The mechanism is not fully understood, but chronic lithium treatment decreases
neostriatal dopaminergic activity, probably through a direct action on the G protein and the capacity of the G
proteins, once activated, to stimulate adenyl cyclase (Carli et al, 1994). Hyperglycemic reactions have also
occurred during combined phenothiazine and lithium use (Zall et al, 1968).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Monitor patients closely for any signs of toxicity or extrapyramidal symptoms,
especially if high doses of dopamine-2 antagonists, particularly haloperidol, and lithium are used. Serum
lithium levels should be monitored periodically. Some clinicians advocate maintaining levels in the low
therapeutic range.
7) Probable Mechanism: unknown
8) Literature Reports
a) Concomitant haloperidol and lithium therapy has resulted in symptoms of encephalopathy,
confusion, extrapyramidal symptoms, and fever in several patients with mania (Cohen & Cohen, 1974;
Loudon & Waring, 1976; Thomas, 1979). Irreversible neurological injuries have been reported (Sandyk
& Hurwitz, 1983; Keitner & Rahman, 1984).
b) Seizures, encephalopathy, delirium, and abnormal EEG occurred in four patients during combined
lithium and thioridazine therapy (Spring, 1979). Serum lithium levels were below 1 mEq/L at the time of
the toxic reaction in all cases. All patients had previously tolerated lithium in combination with another
phenothiazine. Three of these patients developed symptoms within eight days of initiating combination
therapy.
c) The addition of lithium to neuroleptic therapy exacerbated extrapyramidal symptoms (EPS) in a
small study (Addonizio et al, 1988). The patients had received at least five days of treatment with either
oral thiothixene, haloperidol, or fluphenazine in mean doses of 607.5 chlorpromazine equivalents prior
to initiation of the lithium and were experiencing drug-induced extrapyramidal symptoms. Oral lithium
was added when clinically indicated in sufficient doses to achieve a therapeutic serum concentration.
The maximum levels attained were 0.65 to 1.27 mEq/L. The EPS ratings increased in all ten patients
following the addition of lithium. However, only three patients developed marked symptoms and no
patient developed lithium toxicity. Significantly increased symptoms included gait, shoulder shaking,
elbow rigidity, and tremor.
d) Ten patients treated with clozapine and lithium were studied (Blake et al, 1992). Of the ten patients,
Exhibit E.18, page 39
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 40 of 84
Page 200 of 244
four experienced significant neurologic effects, including jerking of limbs, facial spasms and tics, tremor
of hands and arms, tongue twitching, and stumbling gait. One of these also experienced delirium. These
effects reversed when lithium was discontinued or given at a lower dose. On rechallenge, one of two
patients suffered recurrence of symptoms. By keeping serum lithium no greater than 0.5 mEq/L,
clozapine could be safely coadministered.
e) Chlorpromazine serum levels can be significantly reduced in the presence of lithium treatment. If
used concurrently, abrupt cessation of lithium may result in rebound elevation of chlorpromazine levels,
resulting in chlorpromazine toxicity. In patients on a lithium-chlorpromazine combination, abrupt
withdrawal of the lithium may precipitate chlorpromazine cardiotoxicity. In this report, such toxicity was
manifested as sudden ventricular fibrillation associated with prolongation of the QTc interval.
Hypotension and EPS are also possible in this situation (Stevenson et al, 1989).
f) However, other data do not support that such adverse events are frequent or indeed causally related
to combination therapy. Combination of dopamine antagonist antipsychotic drugs and lithium have been
used successfully in many patients with manic-depressive illness. It has been proposed that the
interaction may only become significant with very high doses of one or both drugs or with failure to
discontinue dosing in the presence of toxic symptoms (Miller & Menninger, 1987).
g) A 69-year-old patient with oxygen-dependent chronic obstructive pulmonary disorder and a 25-year
history of bipolar disorder was started on risperidone 3 mg for the treatment of new-onset auditory and
visual hallucinations. She had also been maintained on a regimen of lithium (450 mg daily) for more
than 10 years. In addition, she was given amantadine (100 mg twice daily) for tremor. Three weeks after
the start of risperidone, the patient experienced a decline in mental status in addition to dizziness,
worsening tremors, nausea and vomiting, polyuria, depression, and visual and auditory hallucinations.
She was then admitted to the hospital for delirium. Her lithium serum level was 1.36 mEq/L at the time
of the admission. All medications were discontinued. Although her lithium level decreased to 0.41
mEq/L, she continued to experience profound delirium, tremors, lethargy, and hallucinations for almost
one week. After she started to respond to commands, she was restarted on lithium (300 mg at bedtime)
because of the onset of mild hypomania. Five days later, she was discharged with a regimen of lithium
and low-dose lorazepam for treatment of insomnia. It is suggested that delirium could have been
caused by the concurrent use of lithium and risperidone. Other factors could also have caused delirium,
such as the patient's serum lithium level and the underlying pulmonary pathology. In addition,
amantadine, which facilitates the release of presynaptic dopamine and has a mild anticholinergic effect,
may have contributed (Chen & Cardasis, 1996).
3.5.1.BV Lithospermum
1) Interaction Effect: increased dopaminergic side effects
2) Summary: Theoretically, the dopamine agonist activity of lithospermum may add to that of other
dopamine agonists, increasing the risk of dopaminergic adverse effects. Lithospermum likely decreases
prolactin secretion via dopamine stimulation (Sourgens et al, 1982a). Animal data suggest that the effect
occurs rapidly within 3 hours after injection, subsiding within 6 to 9 hours (Sourgens et al, 1980a). The
magnitude and clinical significance of this phenomenon has yet to be determined in humans. Furthermore, it
is not known if the ability to stimulate dopamine receptors is limited to the hypothalamic region or if such an
effect will be noted elsewhere (i.e., if patients with psychosis will experience worsening of their condition due
to dopamine stimulation secondary to lithospermum). Caution is recommended until the effects on humans
and possible implications of a drug-herb interaction with dopamine agonists can be fully determined.
3) Severity: minor
4) Onset: rapid
5) Substantiation: theoretical
6) Clinical Management: Avoid concomitant use of lithospermum with phenothiazines. If the patient chooses
to take lithospermum, monitor closely for symptoms of additive dopamine agonism such as nausea,
headache, dizziness, fatigue, vomiting, and postural hypotension.
7) Probable Mechanism: additive dopaminergic effect
8) Literature Reports
a) Administration of freeze dried extracts (FDE) of Lithospermum officinale (Boraginaceae) by
intravenous injection to rats resulted in reduced prolactin serum levels and hypophyseal stores. When
administered diluent, prolactin levels decreased from 36 +/- 8 nanograms/milliliter (ng/mL) serum to 10
+/- 4 ng/mL serum (p less than 0.005) when administered Lithospermum officinale FDE (40 milligrams
(mg)/100 grams body weight) within 3 hours post intravenous administration. The authors concluded
that Lithospermum officinale possibly impacted prolactin secretion at the hypothalamic site via
dopamine stimulation (Sourgens et al, 1982).
b) Prolactin levels decreased rapidly below basal values in rats within the first 3 hours following a
single intravenous injection of Lithospermum officinale. Prolactin levels returned to control levels within
6 to 9 hours after the injection (Sourgens et al, 1980).
3.5.1.BW Lorcainide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Class I antiarrhythmic agents may prolong the QT interval in some patients, which may result
in ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Although pharmacokinetic studies
Exhibit E.18, page 40
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 41 of 84
Page 201 of 244
between thioridazine and other drugs which prolong the QT interval have not been performed, an additive
effect cannot be excluded. Therefore, the concurrent administration of thioridazine with a Class I
antiarrhythmic agent is contraindicated (Prod Info Rythmol(R), 2002; Prod Info Mellaril(R), 2002; Prod Info
Tambocor(R), 1998).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval, such as Class I antiarrhythmic agents, is contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.BX Lubeluzole
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, thioridazine should not be
coadministered with other drugs which are also known to prolong the QTc interval, including lubeluzole
(Prod Info Mellaril(R), 2000t).
3) Severity: contraindicated
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval is contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.BY Lumefantrine
1) Interaction Effect: an increased risk of QT interval prolongation
2) Summary: Due to the potential for additive effects on QT interval prolongation, concomitant use of
artemether/lumefantrine with drugs that prolong the QT interval should be avoided (Prod Info COARTEM(R)
oral tablets, 2009).
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Coadministration of artemether/lumefantrine with drugs that prolong the QT
interval should be avoided due to the potential for additive effects on QT interval prolongation (Prod Info
COARTEM(R) oral tablets, 2009).
7) Probable Mechanism: additive effects on QT interval prolongation
8) Literature Reports
a) Concurrent administration of a single dose of IV quinine 10 mg/kg with the final dose of a 6-dose
regimen of artemether/lumfantrine did not alter the systemic exposure to quinine, lumefantrine, or
dihydroartemisinin (active metabolite of artemether). Although artemether exposure was decreased, it
was not believed to be clinically significant. The effects on QT prolongation were not reported in this
study (Prod Info COARTEM(R) oral tablets, 2009).
3.5.1.BZ Mefloquine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, the manufacturer of
thioridazine states that concomitant use with other drugs which prolong the QT interval is contraindicated
(Prod Info Mellaril(R), 2000u). Mefloquine was associated with significant QT prolongation in a study of 46
healthy subjects (Davis et al, 1996).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and any other drug which prolongs
the QT interval, such as mefloquine, is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.CA Meperidine
1) Interaction Effect: an increase in central nervous system and respiratory depression
2) Summary: Phenothiazines may potentiate the analgesic effects of meperidine, resulting in CNS
depression, hypotension, and respiratory depression. Several studies report the potentiation of analgesia by
the addition of promethazine, chlorpromazine, and propiomazine to narcotic analgesics (Fromhagen &
Carswell, 1961a; Winne, 1961a; Glessner & Allis, 1964a; Jackson & Smith, 1956; Eisenstein, 1964). Other
studies and reviews however, do not confirm these findings (Dundee, 1963a; Siker et al, 1966; Keats, 1961;
McGee & Alexander, 1979). When administered concomitantly with phenothiazines, the dose of meperidine
may need to be reduced by 25% to 50% (Prod Info Demerol(R), 1997).
3) Severity: moderate
4) Onset: rapid
Exhibit E.18, page 41
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 42 of 84
Page 202 of 244
5) Substantiation: probable
6) Clinical Management: Monitor patients for signs of respiratory depression, CNS depression, and
hypotension. A dosage reduction or discontinuation of one or both drugs may be necessary.
7) Probable Mechanism: additive effects
8) Literature Reports
a) Promethazine and meperidine combinations have been the most widely studied. It has been
concluded from a controlled study in 296 patients during labor that meperidine 50 mg and promethazine
25 mg produced significantly greater analgesia than 50 mg of meperidine alone (Fromhagen &
Carswell, 1961).
b) No difference in analgesic efficacy was found when promethazine 25 mg and meperidine 50 mg was
alternated with meperidine 100 mg in 26 post-surgical patients (Glessner & Allis, 1964).
c) A controlled study in 51 post-operative hemorrhoidectomy patients concluded that injections of 50
mg of meperidine combined with 50 mg of promethazine gave the same amount of pain relief as a 100
mg injection of meperidine (Winne, 1961). Even though these studies were controlled, response to pain
was still subjective in nature and only post-operative pain was being measured. Pain of this type varies
considerably from patient to patient and no definite conclusions can be drawn from these studies.
d) In opposition to these studies is the detailed investigation by other researchers (Dundee, 1963). By
applying various amounts of pressure to the anterior surface of the tibia, they measured the analgesic
effects of 13 phenothiazines given by deep intramuscular injection. Using this technique, promethazine
alone was shown to have an antianalgesic effect (increased the patients' sensitivity to somatic pain). It
was shown that injections of meperidine 100 mg combined with promethazine 50 mg has less analgesic
effect than 100 mg of meperidine alone. Promazine was the only phenothiazine that showed an additive
analgesic effect with meperidine.
e) Arterial blood gases were measured to determine the effect of methotrimeprazine in 31 healthy
volunteers (Zsigmond & Flynn, 1988). Methotrimeprazine, administered alone, caused no significant
respiratory depression but was found to potentiate the respiratory depression caused by meperidine.
When methotrimeprazine (0.15 mg per kg intravenously) was given alone, PaO2, PaCO2, pH, and base
excess remained unchanged. When methotrimeprazine and meperidine were combined, significant
increases in PaCO2 and pH reductions were observed, which confirms the potentiation of meperidineinduced respiratory depression by methotrimeprazine.
f) The pharmacokinetics of meperidine were not significantly altered when chlorpromazine was
administered concomitantly in a two-way crossover study of 10 healthy patients. Subjects were given
meperidine (26 mg per meter squared) with either chlorpromazine (30 mg per meter squared) or
placebo. The effect of chlorpromazine on the serum concentration-time curve and metabolism of
meperidine was investigated in order to determine if concomitant administration of a phenothiazine and
meperidine alters the metabolism of meperidine, resulting in additive CNS and respiratory depression.
When the two drugs were combined, N-demethylation activity was increased as evidenced by elevated
urinary excretion of normeperidine (a toxic metabolite) and normeperidinic acid. Excretion of
normeperidine is slower than that of meperidine, thus repeated dosing of the combination
(chlorpromazine and meperidine) could lead to increased cardiac and central nervous system toxicity
(Stambaugh & Wainer, 1981).
3.5.1.CB Methadone
1) Interaction Effect: an increase in central nervous system and respiratory depression
2) Summary: The concomitant use of methadone and other central nervous system depressants including
phenothiazines (e.g. chlorpromazine, promethazine, thioridazine) may result in additive CNS and respiratory
depressant effects, including hypotension, profound sedation and/or coma (Prod Info METHADOSE(R) oral
concentrate, sugar-free oral concentrate, 2005). Monitor patient carefully for signs of respiratory depression,
CNS depression, and hypotension.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Monitor patients for signs of respiratory depression, CNS depression, and
hypotension.
7) Probable Mechanism: additive effects
3.5.1.CC Methadone
1) Interaction Effect: an increased risk of QTc interval prolongation
2) Summary: Cases of QT interval prolongation and serious arrhythmias, including torsade de pointes, have
been reported with methadone use (Prod Info DOLOPHINE(R) HYDROCHLORIDE oral tablets, 2006).
Treatment with thioridazine has also been associated with QTc prolongation and sudden death due to
torsade de pointes-type arrhythmias. Concurrent administration of methadone and thioridazine is
contraindicated due to the potential for additive effects on QTc interval prolongation (Prod Info Mellaril(R),
2000n).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Concurrent use of methadone and thioridazine is contraindicated due to the
Exhibit E.18, page 42
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 43 of 84
Page 203 of 244
potential for additive effects on QT interval prolongation (Prod Info Mellaril(R), 2000n).
7) Probable Mechanism: additive effects on QTc interval prolongation
3.5.1.CD Metoprolol
1) Interaction Effect: increased plasma levels of metoprolol
2) Summary: Concurrent use of metoprolol, a CYP2D6 enzyme substrate, and thioridazine, a potent
CYP2D6 enzyme inhibitor, may increase metoprolol exposure. Use caution when metoprolol is administered
concomitantly with thioridazine, and monitor closely for metoprolol adverse effects (such as bradycardia)
(Prod Info LOPRESSOR(R) oral tablets, IV injection, 2006).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Coadministration of metoprolol with thioridazine, a potent CYP2D6-inhibitor,
should be approached with caution. Monitor adverse reactions related to metoprolol toxicity, such as
bradycardia (Prod Info LOPRESSOR(R) oral tablets, IV injection, 2006).
7) Probable Mechanism: inhibition of CYP2D6-mediated metoprolol metabolism
3.5.1.CE Metrizamide
1) Interaction Effect: an increased seizure risk
2) Summary: Concomitant administration of metrizamide and phenothiazines has predisposed patients to
metrizamide-induced seizure activity (Hindmarsh & Brucher, 1975a). However, most available data
supporting this interaction is anecdotal in nature, and specific documentation of the interaction is lacking.
Animal studies demonstrate that concurrent administration of phenothiazines and metrizamide results in a
significantly higher frequency of seizures compared to when these drugs are administered alone (Gonsette
& Brucher, 1977a).
3) Severity: major
4) Onset: rapid
5) Substantiation: theoretical
6) Clinical Management: Chlorpromazine (and possibly other phenothiazines) should be discontinued at
least five days prior to using metrizamide. Halothane, isoflurane, or narcotic/relaxant techniques are
appropriate if general anesthesia is necessary in patients receiving metrizamide.
7) Probable Mechanism: decreased seizure threshold
8) Literature Reports
a) A patient who had a seizure after being injected with metrizamide was the only patient in well over
1,000 patients in this series having major complications (Hindmarsh & Brucher, 1975). The patient had
been on chlorpromazine for 4 months due to a psychiatric disorder. Medication was reduced to 50 mg
from his normal 75 mg the day before the metrizamide injection and reduced again to 25 mg the day of
the procedure. This patient had no prior history of epileptic seizures. Three and a half hours after the
administration of metrizamide the patient sustained a grand mal seizure that lasted 1 minute and
stopped without treatment. Five hours after the first attack the patient exhibited a second attack which
was brought under control by 10 mg of diazepam. This was a single case that suggested the possibility
of a correlation between subarachnoid use of metrizamide and phenothiazines.
b) Over 500,000 applications of metrizamide were reviewed (Ahlgren, 1980). There were 42 reported
convulsions after treatment. A causal relationship between phenothiazine pretreatment and
development of seizures could not be established. The author further stated that the addition of
levomepromazine 40 mg may actually decrease the number of side effects such as headaches and
nausea. One study examined 77 patients, 26 receiving pretreatment with levomepromazine and 51
without the medication (Standness, 1982). EEGs were taken before, during and after treatment. There
were no differences between the groups.
c) In a study of rabbits, pericerebral injection of metrizamide and intravenous injection of
chlorpromazine administered separately produced no clinical seizure activity, but the combination
produced clinical seizures in 66% of the animals (Gonsette & Brucher, 1977). Upon histologic
examination, inflammatory reactions were found in 66% of the animals receiving the combination,
compared to 5% seen with chlorpromazine alone and 0% seen with metrizamide alone. Animals
pretreated with phenobarbital were protected from the enhanced seizure activity of the combination
while animals pretreated with diazepam were not.
3.5.1.CF Morphine
1) Interaction Effect: an increase in central nervous system and respiratory depression
2) Summary: The concomitant use of morphine and other central nervous system depressants including
phenothiazines (e.g. chlorpromazine, promethazine, thioridazine) may result in additive CNS and respiratory
depressant effects, including hypotension, profound sedation and/or coma . When administering morphine
and a phenothiazine together, one or both agents dosage should be significantly reduced (Prod Info MS
CONTIN(R) controlled-release oral tablets, 2005). Monitor patient carefully for signs of respiratory
depression, CNS depression, and hypotension.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
Exhibit E.18, page 43
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 44 of 84
Page 204 of 244
6) Clinical Management: Monitor patients for signs of respiratory depression, CNS depression, and
hypotension. A dosage reduction of one or both drugs should be made.
7) Probable Mechanism: additive effects
3.5.1.CG Morphine Sulfate Liposome
1) Interaction Effect: an increase in central nervous system and respiratory depression
2) Summary: The concomitant use of morphine sulfate liposome and other central nervous system
depressants including phenothiazines (e.g. chlorpromazine, promethazine, thioridazine) may result in
additive CNS and respiratory depressant effects, including hypotension, profound sedation and/or coma
(Prod Info DEPODUR(TM) extended release liposome injection, 2005). Monitor patient carefully for signs of
respiratory depression, CNS depression, and hypotension.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Monitor patients for signs of respiratory depression, CNS depression, and
hypotension.
7) Probable Mechanism: additive effects
3.5.1.CH Moxifloxacin
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, thioridazine should not be
coadministered with other drugs which are also known to prolong the QTc interval, including moxifloxacin
(Prod Info Mellaril(R), 2002; Prod Info Avelox(TM), 2000).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval, such as moxifloxacin, is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.CI Nortriptyline
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2001). Tricyclic
antidepressants (TCAs) at therapeutic doses can cause QT prolongation (Marshall & Forker, 1982).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Concurrent administration of a tricyclic antidepressant and thioridazine is
contraindicated.
7) Probable Mechanism: additive effect on QT interval
3.5.1.CJ Octreotide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturers of some phenothiazines state that concomitant use
with other drugs which prolong the QT interval is contraindicated (Prod Info Thioridazine tablets, 2002). QT
prolongation has been observed in patients treated with octreotide (Prod Info Sandostatin(R), 1999). Other
phenothiazines may have similar effects, though no reports are available.
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of octreotide and thioridazine is contraindicated as it
may precipitate QT prolongation.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.CK Ondansetron
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Rarely, and predominantly with the intravenous formulation, transient ECG changes including
QT interval prolongation have occurred with ondansetron (Prod Info ZOFRAN(R) oral tablets, oral solution,
ZOFRAN ODT(R) orally disintegrating tablets, 2006). Thioridazine has been shown to prolong the QTc
interval in a dose related manner, and should be avoided in combination with other drugs that are known to
prolong the QTc interval, including ondansetron (Prod Info Mellaril(R), 2000k).
3) Severity: contraindicated
4) Onset: unspecified
Exhibit E.18, page 44
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 45 of 84
Page 205 of 244
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of ondansetron and agents that may prolong the QT
interval, such as thioridazine, is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.CL Orphenadrine
1) Interaction Effect: decreased phenothiazine serum concentrations, decreased phenothiazine
effectiveness, enhanced anticholinergic effects (ileus, hyperpyrexia, sedation, dry mouth)
2) Summary: The concurrent use of anticholinergic agents (benztropine, orphenadrine, procyclidine,
trihexyphenidyl) to control extrapyramidal side effects may reduce oral absorption of phenothiazines,
antagonize the behavioral and antipsychotic effects of the phenothiazine, and enhance anticholinergic side
effects (Rivera-Calimlim et al, 1976a; Mann & Boger, 1978a; Singh & Kay, 1979; Gershon et al, 1965a;
Buckle & Guillebaud, 1967).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Anticholinergics (benztropine, orphenadrine, procyclidine, trihexyphenidyl) should
not be used routinely with phenothiazine derivatives as prophylaxis against possible extrapyramidal
symptoms; use should be reserved for situations where EPS occur and lowering of the antipsychotic dosage
is not possible. Anticholinergic use should be reevaluated at least every three months.
7) Probable Mechanism: delayed gastric emptying, increased gut wall metabolism of phenothiazine,
decreased absorption
8) Literature Reports
a) The concomitant administration of trihexyphenidyl and chlorpromazine has been shown to result in a
decrease in chlorpromazine plasma levels (Rivera-Calimlim et al, 1973; Gershon et al, 1965). A
crossover controlled study of the chlorpromazine-trihexyphenidyl interaction in psychiatric patients
showed conclusively that trihexyphenidyl lowers plasma levels of chlorpromazine from 13% to 100%
(Rivera-Calimlim et al, 1976). The mechanism by which trihexyphenidyl lowers plasma levels of
chlorpromazine was shown in rats to be an inhibition of gastric emptying by trihexyphenidyl, probably as
a result of its anticholinergic activity (Rivera-Calimlim, 1976). Slow gastric emptying will delay the
transport of chlorpromazine to intestinal absorption sites and favor enhanced gastrointestinal
metabolism.
b) Trihexyphenidyl may also directly reverse some of the therapeutic effects of chlorpromazine. A toxic
psychosis has been commonly reported following usual therapeutic doses of anticholinergic drugs,
particularly when these agents are used in conjunction with other drugs with anticholinergic properties.
Symptoms may include visual hallucinations, confusion, disorientation, speech difficulty, emotional
lability and psychotic thinking (Perry et al, 1985).
c) The chlorpromazine-trihexyphenidyl interaction may also include additive anticholinergic effects
including constipation or paralytic ileus, dry mouth, blurred vision, increased intraocular pressure and
urinary retention (Perry et al, 1985). Hyperpyrexia has been reported, presumably due to blocking of
exocrine sweat glands in combination with the hypothalamic dysregulation produced by antipsychotics
(Mann & Boger, 1978).
d) A significant reduction in fluphenazine serum levels occurred following addition of procyclidine in
patients who were previously well stabilized. Following discontinuation of procyclidine, fluphenazine
serum levels returned to baseline (Bamrah et al, 1986). However, the addition of orphenadrine to
perphenazine therapy resulted in no clinically relevant pharmacokinetic changes in the absorption,
distribution, or elimination of perphenazine (Bolvig Hansen et al, 1979).
3.5.1.CM Oxycodone
1) Interaction Effect: an increase in central nervous system and respiratory depression
2) Summary: The concomitant use of oxycodone and other central nervous system depressants including
phenothiazines (e.g. chlorpromazine, promethazine, thioridazine) may result in additive CNS and respiratory
depressant effects, including hypotension, profound sedation and/or coma . When administering oxycodone
and a phenothiazine together, the oxycodone dose should be reduced by 1/3 to 1/2 (Prod Info OXYCONTIN
(R) controlled release tablets, 2005). Monitor patient carefully for signs of respiratory depression, CNS
depression, and hypotension.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Monitor patients for signs of respiratory depression, CNS depression, and
hypotension. A dosage reduction of 1/3 to 1/2 of oxycodone should be made.
7) Probable Mechanism: additive effects
3.5.1.CN Paliperidone
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2001b). Several
Exhibit E.18, page 45
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 46 of 84
Page 206 of 244
antipsychotic agents have demonstrated QT prolongation including amisulpride (Prod Info Solian(R), 1999),
haloperidol (O'Brien et al, 1999), pimozide (Prod Info Orap(R), 2000), quetiapine (Owens, 2001c),
paliperidone (Prod Info INVEGA(TM) extended-release oral tablets, 2006), risperidone (Duenas-Laita et al,
1999), sertindole (Agelink et al, 2001), sultopride (Lande et al, 1992), ziprasidone (Prod Info GEODON(R)
intramuscular injection, oral capsule, 2005), and zotepine (Sweetman, 2004).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of agents that prolong the QT interval, such as
antipsychotics, and thioridazine, is contraindicated.
7) Probable Mechanism: additive QT prolongation
3.5.1.CO Paroxetine
1) Interaction Effect: an increased risk of thioridazine toxicity, cardiotoxicity (QT prolongation, torsades de
pointes, cardiac arrest)
2) Summary: Paroxetine inhibits the metabolism of thioridazine, possibly through the inhibition of
cytochrome P450 2D6 (CYP2D6) resulting in toxicity. The resulting elevated levels of thioridazine would be
expected to enhance the prolongation of the QT interval and may increase the risk of serious, potentially
fatal, cardiac arrhythmias, such as torsade de pointes-type arrhythmias (Prod Info Paxil(R), 2003; Prod Info
Mellaril(R), 2000p).
3) Severity: contraindicated
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Due to the potential for significant, possibly life-threatening, proarrhythmic effects,
concurrent administration of thioridazine and paroxetine is contraindicated.
7) Probable Mechanism: inhibition of cytochrome P450 2D6-mediated thioridazine metabolism
8) Literature Reports
a) The metabolism of thioridazine is inhibited by drugs such as paroxetine due to reduced cytochrome
P450 2D6 isozyme activity. The elevated levels of thioridazine would be expected to enhance the
prolongation of the QTc interval associated with thioridazine. This, in turn, may increase the risk of
serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes-type arrhythmias (Prod Info
Mellaril(R), 2000o).
3.5.1.CP Pentamidine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturers of some phenothiazines state that concomitant use
with other drugs which prolong the QT interval is contraindicated (Prod Info Thioridazine tablets, 2002).
Torsades de pointes has been associated with pentamidine (Lindsay et al, 1990).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Pentamidine is contraindicated in patients being treated with thioridazine as it may
precipitate QT prolongation.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.CQ Phenobarbital
1) Interaction Effect: decreased phenobarbital or thioridazine effectiveness
2) Summary: Phenobarbital may decrease thioridazine concentrations due to its ability to induce hepatic
microsomal enzymes (Ellenor et al, 1978a). Phenobarbital and thioridazine have also been reported to
produce lower serum levels of both drugs when given concomitantly (Gay & Madsen, 1983a).
3) Severity: moderate
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: If concurrent therapy is required, a dosage adjustment for thioridazine or
phenobarbital may be required in order to maintain or achieve a therapeutic effect.
7) Probable Mechanism: induction of hepatic microsomal enzymes
8) Literature Reports
a) Seven retarded patients on concurrent phenobarbital and thioridazine therapy experienced an
increase in their thioridazine and metabolite levels when phenobarbital was withdrawn. The most likely
explanation is that withdrawal of phenobarbital resulted in a reversal of the phenobarbital-induced
increase in hepatic drug metabolizing enzyme activity (Ellenor et al, 1978).
b) Retarded adults on phenobarbital and thioridazine 100 mg to 200 mg per day were matched to
retarded adults on antiepileptic therapy alone. When given concomitantly, phenobarbital and
thioridazine produced lower serum levels of both drugs than when either drug was given alone. The
presumed mechanism was induction of microsomal enzymes (Gay & Madsen, 1983).
3.5.1.CR Phenylalanine
Exhibit E.18, page 46
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 47 of 84
Page 207 of 244
1) Interaction Effect: increased incidence of tardive dyskinesia
2) Summary: Taking phenylalanine concomitantly with certain neuroleptic drugs may exacerbate tardive
dyskinesia (Gardos et al, 1992a). Abnormal phenylalanine metabolism in certain patients may lead to
phenylalanine accumulation in the brain and in turn, reduced brain availability of other large neutral amino
acids. This may interfere with the synthesis of catecholamines. It was hypothesized that some patients with
depression may have deficient phenylalanine hydroxylase (as in phenylketonuria (PKU)), or deficient
dihydropteridine reductase (as in atypical PKU) (Gardos et al, 1992a).
3) Severity: moderate
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Caution is advised if phenylalanine is administered with a neuroleptic agent.
Monitor the patient closely for signs of tardive dyskinesia.
7) Probable Mechanism: reduced brain availability of other large neutral amino acids and interference with
catecholamine synthesis
8) Literature Reports
a) Phenylalanine tended to increase the incidence of tardive dyskinesia in patients taking neuroleptics
in an open study. Three groups of patients were studied: (1) patients with unipolar depression with
tardive dyskinesia (n=11), (2) patients with no tardive dyskinesia with current or past exposure to
greater than or equal to 100 milligrams (mg) of a chlorpromazine equivalent for at least 3 months
(n=10), and (3) patients with no tardive dyskinesia not previously exposed to a neuroleptic drug (n=10).
Neuroleptic agents were taken during the study by 6 patients in group 1, and 5 patients in group 2.
Patients received powdered phenylalanine 100 mg/kilogram dissolved in orange juice after an overnight
fast. Blood samples were obtained just prior to phenylalanine administration and 2 hours after
administration. Three patients in group 1 (with tardive dyskinesia) had the highest postloading
phenylalanine plasma levels; this group as a whole had higher (though nonsignificant) mean
phenylalanine levels than the other groups. Tardive dyskinesia score (measured using the Abnormal
Involuntary Movements Scale (AIMS)) nonsignificantly increased in group 1. Postloading phenylalanine
level and postloading AIMS scores were significantly positively correlated in group 1 (rs=0.347, p less
than 0.05; Spearman correlation coefficient 0.543, p less than 0.05). Postloading phenylalanine level
and baseline AIMS scores demonstrated a trend toward correlation (rs=0.246, p=0.092; Spearman
correlation coefficient 0.679, p less than 0.05). In all patients, phenylalanine loading increased plasma
phenylalanine levels approximately eight-fold, and plasma tyrosine increased 2.5 times as a result of
conversion of phenylalanine to tyrosine. Plasma levels of competing large neutral amino acids such as
tryptophan decreased slightly (Gardos et al, 1992).
3.5.1.CS Phenytoin
1) Interaction Effect: increased or decreased phenytoin levels and possibly reduced phenothiazine levels
2) Summary: Concurrent phenothiazine and phenytoin therapy has been reported to increase, decrease, or
cause no change in the serum levels of phenytoin (Sands et al, 1987a; Vincent, 1980a; Siris et al, 1974a;
Houghton & Richens, 1975a). In one study, concomitant phenytoin reduced the serum levels of
mesoridazine, but not thioridazine (Linnoila et al, 1980c).
3) Severity: minor
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Consider monitoring phenytoin levels when a phenothiazine is added or
discontinued from therapy; dosage adjustments may be needed in some cases. The patient should also be
observed for any signs of phenytoin toxicity (ataxia, nystagmus, tremor, hyperreflexia), particularly in the
case of adjustments to the phenothiazine dosage. Observe patients for phenothiazine efficacy.
7) Probable Mechanism: induction or inhibition of phenytoin metabolism; induction of phenothiazine
metabolism
8) Literature Reports
a) Compelling data was reported suggesting that phenothiazines as a group decrease serum phenytoin
concentrations, but the effect of individual phenothiazines was not evaluated. A total of 92 cases
(institutionalized patients) who were receiving constant phenytoin doses and who were either initiating,
discontinuing, increasing, or decreasing a phenothiazine were retrospectively reviewed. Approximately
half of the patients received thioridazine, while the other half were about evenly split between
chlorpromazine and mesoridazine. Phenytoin concentrations decreased by 44% (p=0.001) when a
phenothiazine was added; similarly, increases in phenothiazine dose caused a 33% decrease in
phenytoin concentrations (p=0.001). In patients who discontinued a phenothiazine, phenytoin
concentrations increased by 71% (p=0.001); similarly, decreases in phenothiazine dose caused a 55%
increase in phenytoin concentrations (p=0.001). Although the combined results cannot be applied
clinically to a particular phenothiazine, this study does suggest a remarkably strong trend among
phenothiazines which is contrary to some individual case reports. Further study is needed
(Haidukewych & Rodin, 1985a).
b) The effects of concomitant treatment with phenytoin and/or phenobarbital on the steady-state serum
concentrations of haloperidol, thioridazine, and mesoridazine were investigated in two groups of
patients. The investigators found that concomitant anticonvulsant medication significantly reduced the
plasma level of haloperidol and mesoridazine, but not thioridazine (Linnoila et al, 1980b).
Exhibit E.18, page 47
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 48 of 84
Page 208 of 244
3.5.1.CT Pimozide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2001b). Several
antipsychotic agents have demonstrated QT prolongation including amisulpride (Prod Info Solian(R), 1999),
haloperidol (O'Brien et al, 1999), pimozide (Prod Info Orap(R), 2000), quetiapine (Owens, 2001c),
paliperidone (Prod Info INVEGA(TM) extended-release oral tablets, 2006), risperidone (Duenas-Laita et al,
1999), sertindole (Agelink et al, 2001), sultopride (Lande et al, 1992), ziprasidone (Prod Info GEODON(R)
intramuscular injection, oral capsule, 2005), and zotepine (Sweetman, 2004).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of agents that prolong the QT interval, such as
antipsychotics, and thioridazine, is contraindicated.
7) Probable Mechanism: additive QT prolongation
3.5.1.CU Pindolol
1) Interaction Effect: an increased risk of thioridazine toxicity, cardiotoxicity (QT prolongation, torsades de
pointes, cardiac arrest)
2) Summary: Pindolol has been beneficial in the treatment of patients with behavior and management
problems secondary to organic brain disease (Greendyke & Gulya, 1988a). Fluoxetine inhibits the
metabolism of thioridazine, possibly through the inhibition of cytochrome P450 2D6 (CYP2D6) resulting in
toxicity. The resulting elevated levels of thioridazine would be expected to enhance the prolongation of the
QT interval and may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as torsade de
pointes-type arrhythmias (Prod Info Mellaril(R), 2000ab).
3) Severity: contraindicated
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Due to the potential for significant, possibly life-threatening, proarrhythmic effects,
concurrent administration of thioridazine and pindolol is contraindicated.
7) Probable Mechanism: inhibition of cytochrome P450 2D6-mediated thioridazine metabolism
8) Literature Reports
a) Twenty-six male patients with intermittent explosive disorder secondary to organic brain disease
were studied to determine the effect of pindolol and thioridazine coadministration. All patients were
already receiving treatment with thioridazine, haloperidol, phenytoin, or phenobarbital. Pindolol therapy
was started at 5 mg twice daily with total daily increments of 10 mg every three days for a total dose of
40 mg. It was then reduced by 10 mg increments to zero with a reversal of the schedule. Results
showed moderate, dose-related increases in serum levels of thioridazine and two of its metabolites
when coadministered with pindolol. Serum pindolol levels were also higher than expected in patients
receiving thioridazine. No serum level increases were found for phenytoin, phenobarbital, or haloperidol.
This fact led the authors to believe that the elevation in thioridazine and pindolol levels was due to
mutually competitive interference with their hepatic metabolism (Greendyke & Gulya, 1988).
b) The metabolism of thioridazine is inhibited by drugs such as pindolol due to reduced cytochrome
P450 2D6 isozyme activity. The elevated levels of thioridazine would be expected to enhance the
prolongation of the QTc interval associated with thioridazine. This, in turn, may increase the risk of
serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes-type arrhythmias (Prod Info
Mellaril(R), 2000h).
3.5.1.CV Pirmenol
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Class Ia antiarrhythmics have been shown to prolong the QTc interval at the recommended
therapeutic dose. Even though no formal drug interaction studies have been done, the coadministration of
thioridazine with other drugs known to prolong the QTc interval, including Class Ia antiarrhythmic agents, is
not recommended (Prod Info Mellaril(R), 2002a; Prod Info Procanbid(R), 2000; Prod Info Quinaglute(R),
1999; Desai et al, 1981).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of a Class IA antiarrhythmic and thioridazine is
contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.CW Porfimer
1) Interaction Effect: excessive intracellular damage in photosensitized tissues
2) Summary: Coadministration of porfimer with other photosensitizing agents, including phenothiazines,
Exhibit E.18, page 48
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 49 of 84
Page 209 of 244
may increase the severity of photosensitivity reactions and lead to excessive tissue damage (Prod Info
Photofrin(R), 1995). Caution should be used if thioridazine is to be given to patients receiving porfimer for
photodynamic therapy.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Patients who are receiving phenothiazine therapy along with photodynamic
therapy should be counseled to avoid exposure of skin and eyes to direct sunlight or bright indoor light for 30
days after administration of porfimer. Application of sunscreens does not protect against photosensitivity
reactions.
7) Probable Mechanism: additive photosensitizing effects
3.5.1.CX Prajmaline
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Class Ia antiarrhythmics have been shown to prolong the QTc interval at the recommended
therapeutic dose. Even though no formal drug interaction studies have been done, the coadministration of
thioridazine with other drugs known to prolong the QTc interval, including Class Ia antiarrhythmic agents, is
not recommended (Prod Info Mellaril(R), 2002a; Prod Info Procanbid(R), 2000; Prod Info Quinaglute(R),
1999; Desai et al, 1981).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of a Class IA antiarrhythmic and thioridazine is
contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.CY Probucol
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, thioridazine should not be
coadministered with other drugs which are also known to prolong the QTc interval (Prod Info Mellaril(R),
2000j). Probucol has been shown to prolong the QTc interval (Gohn & Simmons, 1992; Prod Info Lorelco(R),
1991).
3) Severity: contraindicated
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval, such as probucol, is contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.CZ Procainamide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Class Ia antiarrhythmics have been shown to prolong the QTc interval at the recommended
therapeutic dose. Even though no formal drug interaction studies have been done, the coadministration of
thioridazine with other drugs known to prolong the QTc interval, including Class Ia antiarrhythmic agents, is
not recommended (Prod Info Mellaril(R), 2002a; Prod Info Procanbid(R), 2000; Prod Info Quinaglute(R),
1999; Desai et al, 1981).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of a Class IA antiarrhythmic and thioridazine is
contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.DA Procarbazine
1) Interaction Effect: CNS depression
2) Summary: The combined use of phenothiazines and monoamine oxidase inhibitors (MAOI) has resulted
in prolonged phenothiazine effects (Sjoqvist, 1965). To minimize CNS depression and possible potentiation,
coadministration of procarbazine and phenothiazines should be approached with caution (Prod Info
Matulane(R), 2002).
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: The coadministration of procarbazine and phenothiazines should be approached
with caution.
7) Probable Mechanism: unknown
Exhibit E.18, page 49
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 50 of 84
Page 210 of 244
3.5.1.DB Procaterol
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, thioridazine should not be
coadministered with other drugs which are also known to prolong the QTc interval, including procaterol
(Prod Info Mellaril(R), 2000x).
3) Severity: contraindicated
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval is contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.DC Prochlorperazine
1) Interaction Effect: an increased risk of cardiotoxicity (QT interval prolongation, torsades de pointes,
cardiac arrest)
2) Summary: Because thioridazine may prolong the QT interval and increase the risk of arrhythmias, the
concurrent administration of thioridazine and other phenothiazines is contraindicated (Prod Info Mellaril(R),
2000l). Q and T wave distortions have been observed in patients taking phenothiazines (Prod Info
Compazine(R), 2002a; Prod Info Stelazine(R), 2002a; Prod Info Thorazine(R), 2002a). Other phenothiazines
may have similar effects, though no reports are available.
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of agents that prolong the QT interval, such as
thioridazine and other phenothiazines, is contraindicated.
7) Probable Mechanism: additive effect on QT interval
3.5.1.DD Procyclidine
1) Interaction Effect: decreased phenothiazine serum concentrations, decreased phenothiazine
effectiveness, enhanced anticholinergic effects (ileus, hyperpyrexia, sedation, dry mouth)
2) Summary: The concurrent use of anticholinergic agents (benztropine, orphenadrine, procyclidine,
trihexyphenidyl) to control extrapyramidal side effects may reduce oral absorption of phenothiazines,
antagonize the behavioral and antipsychotic effects of the phenothiazine, and enhance anticholinergic side
effects (Rivera-Calimlim et al, 1976d; Mann & Boger, 1978e; Singh & Kay, 1979b; Gershon et al, 1965e;
Buckle & Guillebaud, 1967b).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Anticholinergics (benztropine, orphenadrine, procyclidine, trihexyphenidyl) should
not be used routinely with phenothiazine derivatives as prophylaxis against possible extrapyramidal
symptoms; use should be reserved for situations where EPS occur and lowering of the antipsychotic dosage
is not possible. Anticholinergic use should be reevaluated at least every three months.
7) Probable Mechanism: delayed gastric emptying, increased gut wall metabolism of phenothiazine,
decreased absorption
8) Literature Reports
a) The concomitant administration of trihexyphenidyl and chlorpromazine has been shown to result in a
decrease in chlorpromazine plasma levels (Rivera-Calimlim et al, 1973b; Gershon et al, 1965d). A
crossover controlled study of the chlorpromazine-trihexyphenidyl interaction in psychiatric patients
showed conclusively that trihexyphenidyl lowers plasma levels of chlorpromazine from 13% to 100%
(Rivera-Calimlim et al, 1973b). The mechanism by which trihexyphenidyl lowers plasma levels of
chlorpromazine was shown in rats to be an inhibition of gastric emptying by trihexyphenidyl, probably as
a result of its anticholinergic activity (Rivera-Calimlim, 1976b). Slow gastric emptying will delay the
transport of chlorpromazine to intestinal absorption sites and favor enhanced gastrointestinal
metabolism.
b) Trihexyphenidyl may also directly reverse some of the therapeutic effects of chlorpromazine. A toxic
psychosis has been commonly reported following usual therapeutic doses of anticholinergic drugs,
particularly when these agents are used in conjunction with other drugs with anticholinergic properties.
Symptoms may include visual hallucinations, confusion, disorientation, speech difficulty, emotional
lability and psychotic thinking (Perry et al, 1985b).
c) The chlorpromazine-trihexyphenidyl interaction may also include additive anticholinergic effects
including constipation or paralytic ileus, dry mouth, blurred vision, increased intraocular pressure and
urinary retention (Perry et al, 1985b). Hyperpyrexia has been reported, presumably due to blocking of
exocrine sweat glands in combination with the hypothalamic dysregulation produced by antipsychotics
(Mann & Boger, 1978d).
d) A significant reduction in fluphenazine serum levels occurred following addition of procyclidine in
patients who were previously well stabilized. Following discontinuation of procyclidine, fluphenazine
Exhibit E.18, page 50
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 51 of 84
Page 211 of 244
serum levels returned to baseline (Bamrah et al, 1986b). However, the addition of orphenadrine to
perphenazine therapy resulted in no clinically relevant pharmacokinetic changes in the absorption,
distribution, or elimination of perphenazine (Bolvig Hansen et al, 1979b).
3.5.1.DE Propafenone
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Class I antiarrhythmic agents may prolong the QT interval in some patients, which may result
in ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Although pharmacokinetic studies
between thioridazine and other drugs which prolong the QT interval have not been performed, an additive
effect cannot be excluded. Therefore, the concurrent administration of thioridazine with a Class I
antiarrhythmic agent is contraindicated (Prod Info Rythmol(R), 2002; Prod Info Mellaril(R), 2002; Prod Info
Tambocor(R), 1998).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval, such as Class I antiarrhythmic agents, is contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.DF Propranolol
1) Interaction Effect: an increased risk of thioridazine toxicity, cardiotoxicity (QT prolongation, torsades de
pointes, cardiac arrest)
2) Summary: In two case reports, large doses of propranolol (more than 400 mg daily) resulted in a 3-fold to
5-fold increase of thioridazine concentration in patients on large doses of thioridazine (more than 500 mg
daily) (Silver et al, 1986). Long-acting propranolol resulted in significant dose-related increases in
thioridazine plasma levels in five patients (Greendyke & Kanter, 1987). Fluoxetine inhibits the metabolism of
thioridazine, possibly through the inhibition of cytochrome P450 2D6 (CYP2D6) resulting in toxicity. The
resulting elevated levels of thioridazine would be expected to enhance the prolongation of the QT interval
and may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes-type
arrhythmias (Prod Info Mellaril(R), 2000y).
3) Severity: contraindicated
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Due to the potential for significant, possibly life-threatening, proarrhythmic effects,
concurrent administration of thioridazine and propranolol is contraindicated.
7) Probable Mechanism: inhibition of cytochrome P450 2D6-mediated thioridazine metabolism
8) Literature Reports
a) The metabolism of thioridazine is inhibited by drugs such as propranolol due to reduced cytochrome
P450 2D6 isozyme activity. The elevated levels of thioridazine would be expected to enhance the
prolongation of the QT interval associated with thioridazine. This, in turn, may increase the risk of
serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes-type arrhythmias (Prod Info
Mellaril(R), 2000c).
3.5.1.DG Protirelin
1) Interaction Effect: decreased TSH response
2) Summary: Chronic thioridazine therapy in psychiatric patients may significantly decrease the thyroidstimulating hormone (TSH) response to protirelin (Lamberg et al, 1977). Protirelin 200 mcg was
administered intravenously to 10 patients receiving thioridazine 100 mg to 700 mg daily for over one year.
The mean change in serum TSH levels from baseline was 5.8 microunits/mL in patients on thioridazine,
which was significantly less than those seen in healthy controls (12.5 micrograms/mL).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Monitor patients for a decreased response to thyroid-stimulating hormone (TSH).
7) Probable Mechanism: unknown
3.5.1.DH Protriptyline
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2001). Tricyclic
antidepressants (TCAs) at therapeutic doses can cause QT prolongation (Marshall & Forker, 1982).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Concurrent administration of a tricyclic antidepressant and thioridazine is
contraindicated.
Exhibit E.18, page 51
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 52 of 84
Page 212 of 244
7) Probable Mechanism: additive effect on QT interval
3.5.1.DI Quetiapine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2001b). Several
antipsychotic agents have demonstrated QT prolongation including amisulpride (Prod Info Solian(R), 1999),
haloperidol (O'Brien et al, 1999), pimozide (Prod Info Orap(R), 2000), quetiapine (Owens, 2001c),
paliperidone (Prod Info INVEGA(TM) extended-release oral tablets, 2006), risperidone (Duenas-Laita et al,
1999), sertindole (Agelink et al, 2001), sultopride (Lande et al, 1992), ziprasidone (Prod Info GEODON(R)
intramuscular injection, oral capsule, 2005), and zotepine (Sweetman, 2004).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of agents that prolong the QT interval, such as
antipsychotics, and thioridazine, is contraindicated.
7) Probable Mechanism: additive QT prolongation
3.5.1.DJ Quinidine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Class Ia antiarrhythmics have been shown to prolong the QTc interval at the recommended
therapeutic dose. Even though no formal drug interaction studies have been done, the coadministration of
thioridazine with other drugs known to prolong the QTc interval, including Class Ia antiarrhythmic agents, is
not recommended (Prod Info Mellaril(R), 2002a; Prod Info Procanbid(R), 2000; Prod Info Quinaglute(R),
1999; Desai et al, 1981).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of a Class IA antiarrhythmic and thioridazine is
contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.DK Ranolazine
1) Interaction Effect: an increase in thioridazine serum concentration and an increased risk of cardiotoxicity
(QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Ranolazine, and/or its metabolites, partially inhibit cytochrome P450-2D6-mediated
thioridazine metabolism resulting in increased thioridazine exposure. Ranolazine and thioridazine have been
shown to increase QTc interval in a dose-dependent manner. Concurrent administration of ranolazine and
thioridazine is contraindicated (Prod Info thioridazine hcl oral tablets, 2003).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Using ranolazine and thioridazine together is contraindicated due to the additive
effects on QTc prolongation.(Prod Info thioridazine hcl oral tablets, 2003).
7) Probable Mechanism: ranolazine inhibition of cytochrome P450-2D6-mediated metabolism of thioridazine
and additive effects on QTc prolongation
3.5.1.DL Rilonacept
1) Interaction Effect: altered thioridazine plasma concentrations
2) Summary: In states of chronic inflammation, the formation of CYP450 enzymes is suppressed by
increased levels of cytokines such as interleukin-1 (IL-1). Upon administration of an IL-1 blocker, such as
rilonacept, the formation of CYP450 enzymes could be normalized. In patients receiving CYP450 substrates
with a narrow therapeutic index concomitantly, such normalization may have a clinically relevant effect on
the CYP450 substrate levels. If rilonacept therapy is initiated in a patient being treated with a CYP450
substrate that has a narrow therapeutic index, such as thioridazine, the therapeutic effect of thioridazine
should be monitored and thioridazine dose should be adjusted if necessary (Prod Info ARCALYST(TM)
subcutaneous injection, 2008).
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: If rilonacept therapy is initiated in a patient being treated with a CYP450 substrate
with a narrow therapeutic index, such as thioridazine, monitor for therapeutic effect of thioridazine and adjust
thioridazine dose as needed (Prod Info ARCALYST(TM) subcutaneous injection, 2008).
7) Probable Mechanism: interference with CYP450-mediated thioridazine metabolism
3.5.1.DM Risperidone
Exhibit E.18, page 52
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 53 of 84
Page 213 of 244
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2001b). Several
antipsychotic agents have demonstrated QT prolongation including amisulpride (Prod Info Solian(R), 1999),
haloperidol (O'Brien et al, 1999), pimozide (Prod Info Orap(R), 2000), quetiapine (Owens, 2001c),
paliperidone (Prod Info INVEGA(TM) extended-release oral tablets, 2006), risperidone (Duenas-Laita et al,
1999), sertindole (Agelink et al, 2001), sultopride (Lande et al, 1992), ziprasidone (Prod Info GEODON(R)
intramuscular injection, oral capsule, 2005), and zotepine (Sweetman, 2004).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of agents that prolong the QT interval, such as
antipsychotics, and thioridazine, is contraindicated.
7) Probable Mechanism: additive QT prolongation
3.5.1.DN Ritonavir
1) Interaction Effect: increased thioridazine serum concentrations and potential toxicity (hypotension,
sedation, extrapyramidal effects, arrhythmias)
2) Summary: Coadministered ritonavir may increase serum concentrations of thioridazine, resulting in
thioridazine toxicity (Prod Info NORVIR(R), 2005).
3) Severity: moderate
4) Onset: rapid
5) Substantiation: theoretical
6) Clinical Management: Use caution and monitor patients for signs and symptoms of neuroleptic toxicity
(hypotension, sedation, extrapyramidal effects, arrhythmias). Reduce doses of thioridazine as required.
7) Probable Mechanism: decreased thioridazine metabolism
3.5.1.DO Roxithromycin
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, thioridazine should not be
coadministered with other drugs which are also known to prolong the QTc interval, including roxithromycin
(Prod Info Mellaril(R), 2000e).
3) Severity: contraindicated
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval is contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.DP Sematilide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although no drug interaction studies have been performed, the manufacturer of thioridazine
states that the concurrent use of thioridazine with other drugs known to prolong the QTc interval is
contraindicated (Prod Info Thioridazine tablets, 2002). Class III antiarrhythmic agents may prolong the QT
interval in some patients, which may result in ventricular tachycardia, ventricular fibrillation, and torsades de
pointes (Yamreudeewong et al, 2003; Prod Info Betapace(R), 2001; Prod Info Corvert(R), 2000; Corey et al,
1999; Karam et al, 1998).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval such as Class III antiarrhythmic agents is contraindicated.
7) Probable Mechanism: additive effect on QT interval
3.5.1.DQ Sertindole
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2001b). Several
antipsychotic agents have demonstrated QT prolongation including amisulpride (Prod Info Solian(R), 1999),
haloperidol (O'Brien et al, 1999), pimozide (Prod Info Orap(R), 2000), quetiapine (Owens, 2001c),
paliperidone (Prod Info INVEGA(TM) extended-release oral tablets, 2006), risperidone (Duenas-Laita et al,
1999), sertindole (Agelink et al, 2001), sultopride (Lande et al, 1992), ziprasidone (Prod Info GEODON(R)
intramuscular injection, oral capsule, 2005), and zotepine (Sweetman, 2004).
3) Severity: contraindicated
Exhibit E.18, page 53
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 54 of 84
Page 214 of 244
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of agents that prolong the QT interval, such as
antipsychotics, and thioridazine, is contraindicated.
7) Probable Mechanism: additive QT prolongation
3.5.1.DR Sotalol
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although no drug interaction studies have been performed, the manufacturer of thioridazine
states that the concurrent use of thioridazine with other drugs known to prolong the QTc interval is
contraindicated (Prod Info Thioridazine tablets, 2002). Class III antiarrhythmic agents may prolong the QT
interval in some patients, which may result in ventricular tachycardia, ventricular fibrillation, and torsades de
pointes (Yamreudeewong et al, 2003; Prod Info Betapace(R), 2001; Prod Info Corvert(R), 2000; Corey et al,
1999; Karam et al, 1998).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval such as Class III antiarrhythmic agents is contraindicated.
7) Probable Mechanism: additive effect on QT interval
3.5.1.DS Sparfloxacin
1) Interaction Effect: prolongation of the QTc interval and/or torsades de pointes
2) Summary: Torsades de pointes has been reported in patients receiving sparfloxacin concomitantly with
disopyramide and amiodarone. The use of sparfloxacin is contraindicated with drugs which produce an
increase in the QTc interval and/or torsades de pointes, including phenothiazines. Sparfloxacin is also
contraindicated in persons with known QTc prolongation (Prod Info Zagam(R), 1998).
3) Severity: contraindicated
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Sparfloxacin is contraindicated in individuals with known QTc prolongation or in
patients being treated concurrently with drugs that are known to increase the QTc interval and/or cause
torsades de pointes.
7) Probable Mechanism: additive effects on QTc prolongation
8) Literature Reports
a) In clinical trials involving 1489 patients with a baseline QTc measurement, the mean prolongation of
the QTc interval at sparfloxacin steady-state was 10 msec (2.5%). Of these subjects, 0.7% had a QTc
interval greater than 500 msec at steady-state. However, no arrhythmic effects were seen in any of the
patients. The magnitude of the QTc effect does not increase with repeated administration of
sparfloxacin, and the QTc interval returns to baseline within 48 hours after discontinuation of
sparfloxacin (Prod Info Zagam(R), 1996).
b) A case of sparfloxacin-induced torsades de pointes is described (Dupont et al, 1996). A 47-year old
woman hospitalized for suppurative otitis media and mastoiditis was treated with sparfloxacin due to an
allergy to betalactam antibiotics. On day six of treatment she felt dizzy and lost consciousness. This
was attributed to torsades de pointes on the cardioscope and was followed by cardiac arrest which
required cardiopulmonary resuscitation. Her pre-treatment electrocardiogram showed QT and QTc
intervals of 0.34 and 0.46 seconds, respectively. An electrocardiogram post-arrest revealed QT and
QTc intervals of 0.35 and 0.60 seconds, respectively. A 24-hour continuous electrocardiography
confirmed numerous episodes of torsades de pointes occurring after episodes of sino-auricular block.
Sparfloxacin was discontinued and the QTc returned to baseline within a week. Upon further testing, it
was determined that the patient suffered from a mild idiopathic long QT syndrome. Due to the onset of
symptoms with administration of sparfloxacin and the relief of symptoms following discontinuation of the
drug, it is highly probable that sparfloxacin contributed to the torsades de pointes.
3.5.1.DT Spiramycin
1) Interaction Effect: cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2000aa). QT prolongation
has been reported with spiramycin (Stramba-Badiale et al, 1997).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of spiramycin and thioridazine is contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.DU Sulfamethoxazole
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
Exhibit E.18, page 54
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 55 of 84
Page 215 of 244
arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2000m). Q and T wave
distortions have been observed in patients taking cotrimoxazole (Lopez et al, 1987). Other phenothiazines
may have similar effects, though no reports are available.
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Due to the potential for additive effects on the QT interval, the concurrent
administration of cotrimoxazole and thioridazine is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.DV Sultopride
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2001b). Several
antipsychotic agents have demonstrated QT prolongation including amisulpride (Prod Info Solian(R), 1999),
haloperidol (O'Brien et al, 1999), pimozide (Prod Info Orap(R), 2000), quetiapine (Owens, 2001c),
paliperidone (Prod Info INVEGA(TM) extended-release oral tablets, 2006), risperidone (Duenas-Laita et al,
1999), sertindole (Agelink et al, 2001), sultopride (Lande et al, 1992), ziprasidone (Prod Info GEODON(R)
intramuscular injection, oral capsule, 2005), and zotepine (Sweetman, 2004).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of agents that prolong the QT interval, such as
antipsychotics, and thioridazine, is contraindicated.
7) Probable Mechanism: additive QT prolongation
3.5.1.DW Sunitinib
1) Interaction Effect: an increased risk of QT interval prolongation
2) Summary: Sunitinib has been associated with prolongation of the QT interval in a dose dependent
manner, with torsade de pointes occurring in less than 0.1% patients exposed to sunitinib (Prod Info
SUTENT(R) oral capsules, 2008). Thioridazine has also been shown to prolong the QT interval in a dose
dependent manner. Due to the potential for additive effects on the QT interval and increased risk for torsade
de pointes, the concomitant use of thioridazine and other drugs that prolong the QT interval is
contraindicated (Prod Info MELLARIL(R) oral tablet, solution, USP, MELLARIL-S(R) oral suspension, USP,
2000).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Concomitant use of thioridazine and drugs that prolong the QT interval, such as
sunitinib, is contraindicated due to the potential for additive effects on the QT interval and an increased risk
of torsade de pointes (Prod Info MELLARIL(R) oral tablet, solution, USP, MELLARIL-S(R) oral suspension,
USP, 2000).
7) Probable Mechanism: additive effects on the QT interval
3.5.1.DX Tapentadol
1) Interaction Effect: an increase in central nervous system and respiratory depression
2) Summary: The concomitant use of tapentadol with central nervous system depressants including
phenothiazines (e.g. chlorpromazine, promethazine, thioridazine) may result in additive CNS and respiratory
depressant effects, including hypotension, profound sedation and/or coma. When administering tapentadol
and a phenothiazine together, dosage of one or both agents may be reduced (Prod Info tapentadol
immediate release oral tablets, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Consider monitoring the patient for cardiorespiratory depression when tapentadol
and phenothiazines are used in combination. A reduction in dose of one or both drugs may be necessary
(Prod Info tapentadol immediate release oral tablets, 2008).
7) Probable Mechanism: additive effects
3.5.1.DY Tedisamil
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although no drug interaction studies have been performed, the manufacturer of thioridazine
states that the concurrent use of thioridazine with other drugs known to prolong the QTc interval is
contraindicated (Prod Info Thioridazine tablets, 2002). Class III antiarrhythmic agents may prolong the QT
Exhibit E.18, page 55
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 56 of 84
Page 216 of 244
interval in some patients, which may result in ventricular tachycardia, ventricular fibrillation, and torsades de
pointes (Yamreudeewong et al, 2003; Prod Info Betapace(R), 2001; Prod Info Corvert(R), 2000; Corey et al,
1999; Karam et al, 1998).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval such as Class III antiarrhythmic agents is contraindicated.
7) Probable Mechanism: additive effect on QT interval
3.5.1.DZ Telithromycin
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, thioridazine should not be
coadministered with other drugs which are also known to prolong the QTc interval, including telithromycin
(Owens, 2001d; Prod Info Mellaril(R), 2002h).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that may prolong the QT
interval, such as telithromycin, is contraindicated.
7) Probable Mechanism: additive effects on the QT interval
3.5.1.EA Terfenadine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturers of some phenothiazines state that concomitant use
with other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2002f; Prod Info
Serentil(R), 2000). Q and T wave distortions have been observed in patients taking phenothiazines (Prod
Info Compazine(R), 2002b; Prod Info Stelazine(R), 2002b; Prod Info Thorazine(R), 2002b). Other
phenothiazines may have similar effects, though no reports are available. Even though no formal drug
interaction studies have been done, the coadministration of terfenadine and other drugs known to prolong
the QTc interval, including phenothiazines, is contraindicated (Anon, 1997).
3) Severity: contraindicated
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of terfenadine and a phenothiazine is
contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.EB Tetrabenazine
1) Interaction Effect: increased risk of QT interval prolongation
2) Summary: Tetrabenazine causes a small increase in the corrected QT interval. As the degree of
prolongation increases, QT prolongation can develop into torsade de pointes-type VT. The concomitant use
of tetrabenazine with other drugs known for QT prolongation (eg, thioridazine) should be avoided (Prod Info
XENAZINE(R) oral tablets, 2008). In a randomized, double-blind, placebo controlled crossover study of
healthy subjects, the effect of a single 25 mg or 50 mg dose of tetrabenazine on the QT interval was studied
with moxifloxacin as a positive control. The 50 mg dose of tetrabenazine caused an approximate 8
millisecond mean increase in QT (Prod Info XENAZINE(R) oral tablets, 2008).
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Coadministration of tetrabenazine with thioridazine or other drugs that prolong the
QT interval should be avoided due to the potential for additive effects on the QT interval and increased risk
of torsade de pointes (Prod Info XENAZINE(R) oral tablets, 2008). However, if concurrent therapy is
required, monitor patient closely for prolongation of the QT interval.
7) Probable Mechanism: additive effects on QT interval prolongation
3.5.1.EC Tramadol
1) Interaction Effect: an increased risk of seizures
2) Summary: Seizures have been reported in patients using tramadol. The manufacturer of tramadol states
that combining phenothiazine medications with tramadol may enhance the risk of seizures and CNS and
respiratory depression (Prod Info Ultram(R), 1998).
3) Severity: major
4) Onset: rapid
5) Substantiation: theoretical
6) Clinical Management: Caution should be used if tramadol is to be administered to patients receiving
phenothiazine therapy. If possible, avoid this combination, especially in patients with underlying conditions
Exhibit E.18, page 56
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 57 of 84
Page 217 of 244
that might predispose to seizures.
7) Probable Mechanism: unknown
3.5.1.ED Trazodone
1) Interaction Effect: hypotension
2) Summary: Concomitant administration of trazodone with chlorpromazine or trifluoperazine resulted in
additive hypotensive effects in two case reports. Withdrawal of trazodone resulted in resolution of the
hypotension (Asayesh, 1986).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Monitor blood pressure, particularly in patients who might be sensitive to this
effect. Advise patient to rise slowly from laying or sitting position.
7) Probable Mechanism: additive hypotensive effects
8) Literature Reports
a) In one study, 11 depressed patients received trazodone 150 mg or 300 mg at bedtime for one to 18
weeks. In addition, thioridazine 40 mg daily was given for one week, and blood samplings were
obtained prior to and after the coadministration. Thioridazine significantly increased plasma
concentrations of both trazodone and m-chlorophenylpiperazine, the active metabolite of trazodone.
These results suggest the involvement of cytochrome P4502D6 (CYP2D6) in the metabolism of
trazodone, since thioridazine is a known inhibitor of this isozyme (Yasui et al, 1995).
3.5.1.EE Trifluoperazine
1) Interaction Effect: an increased risk of cardiotoxicity (QT interval prolongation, torsades de pointes,
cardiac arrest)
2) Summary: Because thioridazine may prolong the QT interval and increase the risk of arrhythmias, the
concurrent administration of thioridazine and other phenothiazines is contraindicated (Prod Info Mellaril(R),
2000l). Q and T wave distortions have been observed in patients taking phenothiazines (Prod Info
Compazine(R), 2002a; Prod Info Stelazine(R), 2002a; Prod Info Thorazine(R), 2002a). Other phenothiazines
may have similar effects, though no reports are available.
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of agents that prolong the QT interval, such as
thioridazine and other phenothiazines, is contraindicated.
7) Probable Mechanism: additive effect on QT interval
3.5.1.EF Trihexyphenidyl
1) Interaction Effect: decreased phenothiazine serum concentrations, decreased phenothiazine
effectiveness, enhanced anticholinergic effects (ileus, hyperpyrexia, sedation, dry mouth)
2) Summary: The concurrent use of anticholinergic agents (benztropine, orphenadrine, procyclidine,
trihexyphenidyl) to control extrapyramidal side effects may reduce oral absorption of phenothiazines,
antagonize the behavioral and antipsychotic effects of the phenothiazine, and enhance anticholinergic side
effects (Rivera-Calimlim et al, 1976c; Mann & Boger, 1978c; Singh & Kay, 1979a; Gershon et al, 1965c;
Buckle & Guillebaud, 1967a).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Anticholinergics (benztropine, orphenadrine, procyclidine, trihexyphenidyl) should
not be used routinely with phenothiazine derivatives as prophylaxis against possible extrapyramidal
symptoms; use should be reserved for situations where EPS occur and lowering of the antipsychotic dosage
is not possible. Anticholinergic use should be reevaluated at least every three months.
7) Probable Mechanism: delayed gastric emptying, increased gut wall metabolism of phenothiazine,
decreased absorption
8) Literature Reports
a) The concomitant administration of trihexyphenidyl and chlorpromazine has been shown to result in a
decrease in chlorpromazine plasma levels (Rivera-Calimlim et al, 1973a; Gershon et al, 1965b). A
crossover controlled study of the chlorpromazine-trihexyphenidyl interaction in psychiatric patients
showed conclusively that trihexyphenidyl lowers plasma levels of chlorpromazine from 13% to 100%
(Rivera-Calimlim et al, 1976b). The mechanism by which trihexyphenidyl lowers plasma levels of
chlorpromazine was shown in rats to be an inhibition of gastric emptying by trihexyphenidyl, probably as
a result of its anticholinergic activity (Rivera-Calimlim, 1976a). Slow gastric emptying will delay the
transport of chlorpromazine to intestinal absorption sites and favor enhanced gastrointestinal
metabolism.
b) Trihexyphenidyl may also directly reverse some of the therapeutic effects of chlorpromazine. A toxic
psychosis has been commonly reported following usual therapeutic doses of anticholinergic drugs,
particularly when these agents are used in conjunction with other drugs with anticholinergic properties.
Symptoms may include visual hallucinations, confusion, disorientation, speech difficulty, emotional
Exhibit E.18, page 57
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 58 of 84
Page 218 of 244
lability and psychotic thinking (Perry et al, 1985a).
c) The chlorpromazine-trihexyphenidyl interaction may also include additive anticholinergic effects
including constipation or paralytic ileus, dry mouth, blurred vision, increased intraocular pressure and
urinary retention (Perry et al, 1985a). Hyperpyrexia has been reported, presumably due to blocking of
exocrine sweat glands in combination with the hypothalamic dysregulation produced by antipsychotics
(Mann & Boger, 1978b).
d) A significant reduction in fluphenazine serum levels occurred following addition of procyclidine in
patients who were previously well stabilized. Following discontinuation of procyclidine, fluphenazine
serum levels returned to baseline (Bamrah et al, 1986a). However, the addition of orphenadrine to
perphenazine therapy resulted in no clinically relevant pharmacokinetic changes in the absorption,
distribution, or elimination of perphenazine (Bolvig Hansen et al, 1979a).
3.5.1.EG Trimethoprim
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2000m). Q and T wave
distortions have been observed in patients taking cotrimoxazole (Lopez et al, 1987). Other phenothiazines
may have similar effects, though no reports are available.
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Due to the potential for additive effects on the QT interval, the concurrent
administration of cotrimoxazole and thioridazine is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.EH Trimipramine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2001). Tricyclic
antidepressants (TCAs) at therapeutic doses can cause QT prolongation (Marshall & Forker, 1982).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Concurrent administration of a tricyclic antidepressant and thioridazine is
contraindicated.
7) Probable Mechanism: additive effect on QT interval
3.5.1.EI Vasopressin
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Thioridazine and vasopressin have been shown to prolong the QTc interval at the
recommended therapeutic dose (Prod Info Mellaril(R), 2000n; Mauro et al, 1988). Even though no formal
drug interaction studies have been done, the coadministration of drugs known to prolong the QTc interval is
not recommended.
3) Severity: contraindicated
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of drugs that prolong the QT interval, such as
thioridazine and vasopressin, is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.EJ Vitex
1) Interaction Effect: increased dopaminergic side effects
2) Summary: Theoretically, the dopamine agonist activity of Vitex may add to that of other dopamine
agonists, increasing the risk of dopaminergic adverse effects. Vitex has been effective in alleviating luteal
phase defects due to hyperprolactinemia and in relieving symptoms related to premenstrual tension
syndrome (Milewicz et al, 1993a; Lauritzen et al, 1997a). Vitex reduced prolactin secretion in humans
(Milewicz et al, 1993a). In vitro, Vitex inhibited prolactin release by binding to the D2 receptor (Jarry et al,
1994a).
3) Severity: minor
4) Onset: delayed
5) Substantiation: established
6) Clinical Management: Avoid concomitant use of Vitex with phenothiazines. If the patient chooses to take
Vitex, monitor closely for symptoms of additive dopamine agonism such as nausea, headache, dizziness,
fatigue, vomiting, and postural hypotension.
7) Probable Mechanism: additive dopaminergic effect
Exhibit E.18, page 58
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 59 of 84
Page 219 of 244
8) Literature Reports
a) Vitex agnus castus effectively normalized prolactin release in a randomized double-blind, placebocontrolled trial of 52 women with luteal phase defects due to latent hyperprolactinemia. Administration of
Vitex agnus castus 20 mg daily for three months reduced prolactin release (from 23.7 to 22.5 nanogram
(ng)/mL; p equal to 0.23), normalized shortened luteal phases (from 5.5 days to 10.5 days; p less than
0.005), and eliminated deficits in luteal progesterone synthesis (from 2.46 ng/mL to 9.69 ng/mL; p less
than 0.001). No side effects were noted (Milewicz et al, 1993).
b) Vitex agnus castus and pyridoxine caused a similar reduction on the premenstrual tension scale
(PMTS) in a randomized, controlled trial of 127 women with PMTS. Patients taking Vitex agnus castus
(Agnolyt(R)) experienced more relief from breast tenderness, inner tension, headache, edema,
constipation, and depression than those taking pyridoxine. Patients in the Vitex agnus castus group
receive one capsule of Agnolyt(R) and one placebo capsule daily for 3 menstrual cycles. Patients in the
pyridoxine group received one placebo capsule twice daily on days 1-15 of the menstrual cycle and
pyridoxine 100 mg twice daily on days 16 to 35 of the menstrual cycle for 3 menstrual cycles.
Unspecified gastrointestinal disturbances occurred in the treatment group along with two cases of skin
reaction and one transient headache (Lauritzen et al, 1997).
c) In vitro, Vitex (Agnus castus) was found to bind to the D2 receptor in rat pituitary cell cultures. Basal
prolactin release was significantly inhibited by 0.5 milligram (mg) and 1 mg of Vitex extract/mL culture
medium (p less than 0.05). Agnus castus extract doses from 0.125 mg/mL to 1 mg/mL significantly
suppressed prolactin release in cells stimulated by thyrothropin releasing hormone (TRH) (p less than
0.05). Dopaminergic action was demonstrated in the rat corpus striatum membrane dopamine receptor
assay. Agnus castus extract did not affect basal luteinizing hormone (LH) or follicle-stimulating hormone
(FSH), indicating selectivity for prolactin secretion, and not generalized inhibition of pituitary hormone
secretion. The effect was not due to a cytotoxic effect as demonstrated by the lack of effect on the MTTconversion test. The authors concluded that Agnus castus exerted its prolactin inhibiting effect via
stimulation of D2 receptors in the pituitary (Jarry et al, 1994).
3.5.1.EK Ziprasidone
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (Prod Info Mellaril(R), 2001b). Several
antipsychotic agents have demonstrated QT prolongation including amisulpride (Prod Info Solian(R), 1999),
haloperidol (O'Brien et al, 1999), pimozide (Prod Info Orap(R), 2000), quetiapine (Owens, 2001c),
paliperidone (Prod Info INVEGA(TM) extended-release oral tablets, 2006), risperidone (Duenas-Laita et al,
1999), sertindole (Agelink et al, 2001), sultopride (Lande et al, 1992), ziprasidone (Prod Info GEODON(R)
intramuscular injection, oral capsule, 2005), and zotepine (Sweetman, 2004).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of agents that prolong the QT interval, such as
antipsychotics, and thioridazine, is contraindicated.
7) Probable Mechanism: additive QT prolongation
3.5.1.EL Zolmitriptan
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Even though no formal drug interaction studies have been done, the manufacturer of
thioridazine states that thioridazine should not be coadministered with other drugs which are also known to
prolong the QTc interval (Prod Info Thioridazine tablets, 2002). Zolmitriptan has been shown to prolong the
QTc interval at the recommended therapeutic dose (Prod Info Zomig(R), 2001).
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of thioridazine and agents that prolong the QT
interval, such as zolmitriptan, is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.EM Zotepine
1) Interaction Effect: increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Although no drug interaction studies have been performed, the manufacturer of thioridazine
states that coadministration of thioridazine with drugs known to prolong the QTc interval is contraindicated
(Prod Info Mellaril(R), 2001a). Zotepine can prolong the QTc interval (Sweetman, 2004).
3) Severity: contraindicated
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Concurrent administration of agents that prolong the QT interval, such as zotepine
and thioridazine, is contraindicated.
Exhibit E.18, page 59
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady
7/7/2009
MICROMEDEX® Healthcare Series : Document
Case 3:09-cv-00080-TMB Document 78-27
Filed 03/24/2010
Page 60 of 84
Page 220 of 244
7) Probable Mechanism: additive effects on QT prolongation
8) Literature Reports
a) Since zotepine can prolong the QT interval it is recommended that an ECG is performed before
starting treatment. Patients with pre-existing prolongation of the QT interval should not be given
zotepine (Sweetman, 2004).
3.5.1.EN Zotepine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with
other drugs which prolong the QT interval is contraindicated (